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Montse Sanchez-Cespedes
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MA04 - Models and Biomarkers (ID 122)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 12
- Now Available
- Moderators:Montse Sanchez-Cespedes, Kwok-kin Wong
- Coordinates: 9/08/2019, 13:30 - 15:00, Interlaken (1988)
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MA04.01 - Development of an in Vivo Platform to Identify Novel Mechanisms Governing Lung Cancer Response to Immunotherapy (Now Available) (ID 714)
13:30 - 15:00 | Presenting Author(s): Kelsie L Thu | Author(s): Shawn P Kubli, Andrew C Wakeham, Andrew J Elia, Tak Mak
- Abstract
- Presentation
Background
Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for the treatment of advanced stage lung cancer. While these agents elicit durable responses in some patients, most do not respond. An improved understanding of the mechanisms governing ICI response in a complex in vivo setting has potential to reveal novel therapeutic combinations to enhance ICI efficacy and associated biomarkers indicative of response. We have developed a syngeneic lung tumour model for in vivo CRISPR/Cas9 screens to deduce novel tumour-intrinsic mediators of response to anti-PD1 therapy.
Method
To delineate physiologically relevant ICI response mechanisms, an in vivo, syngeneic and orthotopic lung tumour model with an intact immune system is required. For this purpose, we have developed the KRAS-mutant Lewis Lung Carcinoma (LLC) model. Flow cytometry and immunohistochemistry were used to characterize immune cell composition in resected tumours and in vivo experiments were conducted to determine the effects of anti-PD1 treatment on LLC tumour growth.
Result
Luciferase-tagged LLC cells were implanted into the lungs of syngeneic C57BL/6 mice using orthotopic injection and mice reached humane endpoints 10-14 days post injection. Immunophenotyping of dissociated tumours revealed changes in the proportions of myeloid and lymphocyte populations relative to tumour-naïve lungs. CD8+ T-cells were present and tumour cells expressed PDL1 suggesting LLC has the capacity to respond to ICI. Consistent with these observations, orthotopic LLC growth was delayed in mice treated with anti-PD1 therapeutic antibody compared to anti-IgG2a isotype control, demonstrating that LLC is an appropriate model for identifying mechanisms that confer sensitivity and/or resistance to ICI therapy. Based on these findings, we generated LLC-Luciferase cells stably expressing Cas9. Since genome-wide screens are not feasible with this in vivo tumour model, we are synthesizing a custom, focussed guide RNA (gRNA) library. Genomic analyses have identified ~500 candidate immunomodulatory genes expressed in LLC and clinical lung tumours that will be targeted to determine the effects of inactivating these candidates on anti-PD1 response.
Conclusion
This platform will enable high-throughput genetic screens to elucidate novel tumour-intrinsic determinants of ICI response in vivo. Our discoveries will have potential to inform novel biomarkers predictive of response, and putative targets for new combination therapies to enhance the anti-tumour effects of ICIs. Collectively, this work will improve our understanding of the biological mechanisms governing ICI sensitivity, thereby stimulating the development of new strategies to maximize therapeutic benefit from ICIs in lung cancer patients.
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MA04.02 - Molecular Profiling of Adenocarcinoma and Squamous Cell Lung Cancer at Single Cell Resolution (Now Available) (ID 1358)
13:30 - 15:00 | Presenting Author(s): fengying Wu | Author(s): Yayi He, Zhou Yiqi, Anwen Xiong, Jia Yu, Wei Li, Nan Fang, Caicun Zhou
- Abstract
- Presentation
Background
Adenocarcinoma and squamous are two main subgroups of lung cancer: adenocarcinoma (ADC) accounts for 30-50% and squamous cell carcinoma (SCC) accounts for nearly 30% of all cases respectively. ADC and SCC have different pathological phenotypes and respond differently to various therapies, including immunotherapy. However, the underlying molecular mechanism of such differentiated drug responses still needs to be further characterized.
Method
To achieve high resolution of both tumor cells and their tumor microenvironment (TME), we used single cell RNA sequencing method to characterize ADC and SCC tumors from Stage IV NSCLC patients. Tissue biopsy samples from 21 patients (12 patients with ADC, 9 with SCC) were collected. For each sample, single cell RNA sequencing was performed on an average of 1930 cells. A graph-based clustering approach was used to classify cells into different cell types based on their gene expression patterns. The cellular subtypes of both cancer cells and TME in ADC and SCC samples were analyzed.
Result
ADC and SCC show distinct patterns at single cell resolution. Cancer cells from all ADC patients form two closely related clusters, while cancer cells from SCC patients show high intra-and inter-patient heterogeneity. Gene Ontology (GO) analysis demonstrated that ADC samples are enriched in genes of neutrophil degranulation and activation, while SCCs are enriched in genes related to epidermal cell differentiation and glutathione metabolic process. Genes related to cancer progression and metastasis, such as LSD1 and FASCIN, are normally expressed at higher level in SCC than in ADC. Furthermore, ADC samples contain higher percentage of a specific myeloid cell population, while SCC has higher percentage of fibroblasts, demonstrating the difference also in TMEs of ACD versus SCC.
Conclusion
The significantly higher level of heterogeneity for SCC can be a possible reason for poor responses to standard lung cancer therapies, including immunotherapy. Accurate characterization of SCC with single cell resolution could hold the key to more effective therapeutic strategies.
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MA04.03 - Lung Tumorspheres Characterization Reveals Cancer Stem-Like Cells Potential Targets and Prognostic Markers in Non-Small Cell Lung Cancer (Now Available) (ID 2269)
13:30 - 15:00 | Presenting Author(s): Alejandro Herreros-Pomares | Author(s): Eloisa Jantus-Lewintre, Silvia Calabuig-Fariñas, Juan Diego De-Maya-Girones, Rut Lucas, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Eva Escorihuela, María Dolores Chiara, Elena Durendez-Saez, Carolina Gandia, Rafael Sirera, Rosa Farràs, Carlos Camps
- Abstract
- Presentation
Background
Non-small cell lung cancer (NSCLC) is the leading cause of death cancer-related worldwide due to late diagnosis and high resistance against treatments. This resistance has been associated to cancer stem-like cells (CSCs), a highly tumorigenic subpopulation for which the identification of targets and biomarkers is still under development.
Method
Tissue samples from 8 NSCLC patients were successfully established and cultured using a sphere-forming assay for CSCs enrichment. Adherent counterparts were used as differentiated control cells. Proliferation, chemorresistance, invasion and differentiation capacities were tested in vitro, whereas tumor initiation capacity was determined in vivo. The expression of 44 CSCs-related genes was assessed by qPCR and protein expression of the best contributors to distinguish adherent cells from tumorspheres was determined by immunoblot and immunofluorescence. The prognostic role of these genes was evaluated in a cohort of 661 resected NSCLC patients from TCGA and validated in an independent cohort of 114 resected lung adenocarcinoma patients.
Result
Patient-derived tumorspheres showed unlimited exponential growth, high resistance against chemotherapy, great invasion and differentiation capacities in vitro in addition to a higher tumorigenic potential than adherent cells in vivo. The expression of 17 genes was significantly overexpressed in lung tumorspheres, being NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 the best contributors. Proteins encoded by these genes were consistently increased in tumorspheres from adenocarcinoma patients and showed differential localization and expression patterns. The expression of CDKN1A, SNAI1 and ITGA6 was associated to prognosis based on Cox regression analysis (Z-score > 1.5), so their absolute regression coefficients from a multivariate model were used to calculate a gene expression score. Kaplan-Meier survival analysis showed that patients with high score have shorter OS in the entire cohort [37.7 vs. 60.4 mo., p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo., p = 0.003], but not in squamous cell carcinoma one. Multivariate analysis indicated that this gene expression score was an independent biomarker of prognosis for OS in both, the entire cohort [HR: 1.498; 95% CI, 1.167-1.922; p = 0.001] and the adenocarcinoma subcohort [HR: 1.869; 95% CI, 1.275-2.738; p = 0.001]. The prognostic value of this score was confirmed in an independent cohort of 114 lung adenocarcinoma patients (42.90 vs. NR mo, p = 0.020).
Conclusion
Proteins encoded by NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 are potential targets against lung CSCs. Elevated gene expression levels of CDKN1A, SNAI1 and ITGA6 are associated with worse prognosis.
Funded by CB16/12/00350 from CIBEROnc, PI12-02838, and PI15-00753 from ISCIII and Fundacion Arnal Planelles.
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MA04.04 - Discussant - MA04.01, MA04.02, MA04.03 (Now Available) (ID 3730)
13:30 - 15:00 | Presenting Author(s): David Santamaria
- Abstract
- Presentation
Abstract not provided
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MA04.05 - Deciphering the Molecular Mechanisms Underlying the Progression of Bronchial Premalignant Lesions (Now Available) (ID 2108)
13:30 - 15:00 | Presenting Author(s): Evgeny V. Denisov | Author(s): Polina A. Gervas, Anastasia A. Ponomaryova, Anastasia A. Schegoleva, Tatiana S. Gerashchenko, Artem M. Kiselev, German M. Demidov, Alexey A. Zarubin, Liliya S. Lyapunova, Sergey P. Kovalenko, Olga V. Cheremisina, Sergey A. Tuzikov, Olga V. Pankova, Nadezhda V. Cherdyntseva, Vladimir M. Perelmuter
- Abstract
- Presentation
Background
The mechanisms underlying the progression of bronchial lesions to squamous cell lung cancer remain undefined. Previously, we hypothesized that bronchial lesions presented individually or combined with each other in the bronchi of non-small cell lung cancer (NSCLC) patients mirror the different scenarios of the premalignant process: individual basal cell hyperplasia (iBCH) – the stoppage at hyperplasia, BCH plus squamous metaplasia (SM) – the progression of hyperplasia to metaplasia, and SM plus dysplasia – the progression of metaplasia to dysplasia. In this study, we aimed to assess the molecular profile of BCH, SM, and dysplasia depending on their co-occurrence in the bronchi of NSCLC patients and to identify mechanisms that are involved in the different scenarios of the premalignant process.
Method
The samples of lung tissue were obtained at a distance of 4-5 cm from the tumor during surgery of 21 NSCLC patients. Normal bronchial epithelium, BCH, and SM, as well as dysplasia, were isolated from tissue sections using laser microdissection PALM (Carl Zeiss). The microdissected samples underwent whole genome (One Step WGA, Bioron) and transcriptome (Ovation PicoSL WTA System V2, Nugen) amplification and sequenced using the SeqCap EZ Human Oncology Panel (Roche) and profiled using SurePrint G3 Human GE v2 8x60K microarrays (Agilent). Additionally, the samples were sequenced using the Pico Methyl-Seq Library Prep Kit (Zymo Research). Changes in gene expression were confirmed using immunohistochemical staining.
Result
Genetic alterations were observed already at the early stages of the premalignant process in the bronchial epithelium; however, their number varied from sample to sample. For example, one case of BCH showed more than 10 deleterious mutations in the GRM5, MAML2, SP1, ETV4, and other genes, whereas other BCHs carried single alterations. No significant differences were found in the mutational landscape between the iBCH and BCH combined with SM. Bisulfite sequencing demonstrated significant changes in the methylation status of the SAPCD2 and ST14 genes in BCH. Importantly, these changes differed between various forms of BCH. Sequencing of SM and dysplasia is in progress and results will be presented later. Gene expression profiling showed differences in the activity of immune response genes between the iBCH and BCH combined with SM and the cell cycle and cilium assembly genes between SMs co-presented with BCH and dysplasia. Overall, the transcription profile of SM co-presented with BCH was closer to BCHs, whereas SM co-detected with dysplasia was similar to dysplasia. Several genes were identified to be expressed specifically in different forms of BCH and SM, among which CCDC114, MAP7D2, and LIFR were confirmed by immunohistochemistry. The loss of CCDC114 and MAP7D2 in SM may serve as an indicator of its progression to dysplasia.
Conclusion
Taken together, this study demonstrates the significant differences between various types of BCH and SM. These differences support the hypothesis that the isolated and combined forms of the bronchial lesions mirror the different scenarios of the premalignant process as well as explore the mechanisms underlying the progression of hyperplasia and metaplasia to dysplasia.
The study was supported by RFBR (#17-29-06002) and the Russian President Fellowship (#SP-1549.2018.4).
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MA04.06 - Lung Epithelium Whole Transcriptome Signatures That Reflect Incident Lung Cancer Case-Control Status (Now Available) (ID 2526)
13:30 - 15:00 | Presenting Author(s): Simon D Spivack | Author(s): Xiao Dong, Miao Kevin Shi, Weiguo Han, Steven Keller, Alex Maslov, Yousin Suh, Jan Vijg
- Abstract
- Presentation
Background
BACKGROUND: Focusing early detection and prevention efforts on those at high risk for lung cancer is central to leveraging such strategies. Notably, that risk persists even after removal of a lung cancer, as reflected in lung recurrences, which are common, and usually occur remote from the surgical removal site. This implies risk for future incident lung cancer is represented in the biology of broad areas of lung epithelium, before, during, and after diagnosis. Given that somatic mutations in the bronchial tree are known to persist for decades, there is a suggestion that smoking transforms the entire epithelium at several somatic and gene regulatory levels. We hypothesize that the normal lung epithelium contains expression and epigenetic epithelial signatures that are representative of donor case-control status, that is poised for carcinogenesis.
Method
METHODS: As a first step, in order to identify differentially expressed genes (DEGs) associated with aging, smoking and cancer case-control status, we analyzed RNA-seq transcriptome data of laser capture microdissected (LCM) bronchial and alveolar epithelium separately, in paired tissue sets of 40- and 74 respective individuals, summarized here. Read count was the main normalization variable. We also measured differentially methylated sites (DME) by whole genome bisulfite genome sequencing (WGBSeq), covering >60% of the genome/methylome [as of this deadline, these methylome data are not yet fully analyzed].
Result
RESULTS: Mean subject age for 77 total subjects was 65 (+/-9.9), 19% current-, 76% former, 5% never smokers. For each cell type, we modeled gene expression level as a result of aging, gender, smoking and case-control status. We put all four clinical variables age, gender, smoking status, case-control status) along with cell type (alveolar/bronchial) into the model, to avoid potential confounding effects. We discovered 175 DEGs discriminating case-control status (FDR p<0.05) in alveolar and bronchial cells combined, and 420 case-control DEGs with bronchial cells alone. Bronchial cells displayed 31 DEGs discriminating current versus former smokers (FDR-adjusted P<0.05). Gene ontology (David) clusters for case-control discrimination in these “normal” bronchial epithelia included energetics pathways (GO 0042776/0006754; ATP biosynthesis) as well as transcriptional and translational regulation pathways; KEGG clusters also included oxidative phosphorylation pathways (hsa00190), among others.
Conclusion
CONCLUSION: There is a donor case-control discriminant expression signature for human lung bronchial captured cells, emphasizing bioenergetically-deranged metabolic pathways, among others. If confirmed in larger studies that measure deranged metabolites directly, metabolomics biomarkers representing bioenergetics and other pathways may serve to define those individuals whose epithelia is tilted toward carcinogenesis, and therefore are at increased risk for lung cancer.
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MA04.07 - Inhibition of CXCR2+ Neutrophil Migration as a Targeted Therapy in KRAS-Driven Lung Adenocarcinoma (Now Available) (ID 2914)
13:30 - 15:00 | Presenting Author(s): Meghan De Meo | Author(s): Roni F. Rayes, Simon Milette, Mara Vagai, Mariana Usatii, Arvind Chandrasekaran, Betty Giannias, France Bourdeau, Christopher Moraes, Sidong Huang, Daniela Quail, Logan Walsh, Veena Sangwan, Nicholas Bertos, Sophie Camilleri-Broet, Philippe Broet, Pierre O Fiset, Jonathan Cools-Lartigue, Lorenzo E. Ferri, Jonathan D. Spicer
- Abstract
- Presentation
Background
Lung adenocarcinoma (LUAD) accounts for 40% of all lung cancer cases. Although driver mutations in the K-RAS oncogene occurs in 25% of all LUAD cases, to date, there are no available targeted therapies. Infiltrating neutrophils in LUAD are indicative of the worst survival outcomes. The C-X-C motif chemokine receptor 2 (CXCR2) mediates their recruitment to the tumour microenvironment where they promote a pro-tumorigenic environment. CXCR2 ligand expression is higher in KRAS-driven LUAD compared to the other most frequently mutated oncogenes. Therefore, we hypothesize that K-RAS-driven LUAD may be the best candidate for a CXCR2 targeted treatment strategy.
Method
The PREdiction of Clinical Outcomes from Genomic Profiles (PRECOG) is a dataset of gene expression and survival outcome. The dataset includes data from approximately 18 000 human patients with 39 different malignancies. The dataset was used to determine whether high neutrophil infiltration, CXCR2 expression and CXCR2 ligand expression were associated with poor survival outcomes in LUAD. A 100 patient LUAD tissue microarray was built and stained for neutrophil elastase and CXCR2 by immunohistochemistry. Kaplan-Meier curves were used determine the effect of high neutrophil or CXCR2+ cell infiltration in the LUAD tumour microenvironment on survival outcome. The Cancer Cell Line Encyclopedia (CCLE) is an online dataset that provides gene expression and genotype data from 947 human cancer cell lines (36 cancer types). Expression data of all LUAD cell lines (n=70) from CCLE was obtained for all known CXCR2 ligands. The expression of CXCR2 ligands in K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines was compared. Microfluidics devices were used to compare the neutrophil recruitment to K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines. The neutrophil recruitment to each of the cell lines was compared in the presence and absence of CXCR2 inhibition.
Result
Using the PRECOG dataset, we found that CXCR2 expression in neutrophils is at least 18-fold greater than its expression in other immune cell types. Using all the LUAD cell lines (n=70) available on the CCLE, we found that K-RAS-driven LUAD is the highest CXCR2 ligand expresser as compared to EGFR, ALK and ROS1-driven LUAD. Moreover, using PRECOG, we found that poorer survival outcome is associated with high expression of eight out of nine known CXCR2 ligands (p < 0.05). In addition, high neutrophil infiltration in LUAD is associated with the worst survival outcome compared to other immune cell infiltrates (p < 0.001). In accordance with the PRECOG data, the presence of infiltrating neutrophils in a 100 patient LUAD tissue microarray is associated with poorer survival outcome when compared to patients with no infiltrating neutrophils (p < 0.05). Neutrophil migration to K-RAS, EGFR, ALK and ROS1-driven LUAD cell lines was examined in microfluidics devices and found to be highest in K-RAS-driven LUAD. CXCR2 inhibition reduced neutrophil migration only in K-RAS-driven lung adenocarcinoma (p < 0.05).
Conclusion
CXCR2 inhibition could be an exciting potential targeted treatment for patients with K-RAS-driven LUAD. CXCR2 inhibition is in clinical trials for metastatic melanoma, pancreatic, breast and head and neck cancer. Current evidence suggests that CXCR2 inhibition is safe and tolerable.
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MA04.08 - Discussant - MA04.05, MA04.06, MA04.07 (Now Available) (ID 3731)
13:30 - 15:00 | Presenting Author(s): Triantafillos (Lakis) Liloglou
- Abstract
- Presentation
Abstract not provided
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MA04.09 - Study of Exosomes in NSCLC for Biomarkers Searching (Now Available) (ID 2417)
13:30 - 15:00 | Presenting Author(s): Elena Durendez-Saez | Author(s): Silvia Calabuig-Fariñas, Cristian Suarez, Marais Mosqueda, Sandra Gallach, Eva Escorihuela, Andrea Moreno, Susana Torres, Alejandro Herreros-Pomares, Álvaro González, Ernesto De La Cueva, Eva Serna, Jesus M Paramio, Eloisa Jantus-Lewintre, Carlos Camps
- Abstract
- Presentation
Background
Exosomes are small membranous vesicles secreted by a most type of cells (especially in tumoral processes), around 40-130 nm of size, that carry relevant information to distant tissues and being able to modulate its physiology. Exosomes have been detected in different clinical samples and may play a key role in NSCLC, participating in several processes such as horizontal transfer of RNA from tumor to microenvironmental cells, angiogenesis, pre-metastatic niche formation, immunosuppression; and could also be key elements in stem cell differentiation (from different origins).
The principal objective of this study was to analyze the exosomes cargo from NSCLC cell lines and primary cultures with diverse characteristics under different growth conditions: suspension cultures with cancer stem cells (CSCs) features and monolayer cultures.
Method
Primary cultures from resected NSCLC patients and NSCLC cell lines were successfully established. Differentiated tumor cells were cultured under adherent conditions (2D) whereas CSCs were established in suspension cultures (3D tumorspheres). Exosomes isolation was performed by ultracentrifugation. Exosomes characterization was carried out through nanovesicles tracking analysis (NTA) and electron microscopy; and the determination of surface markers through immunoblot and flow cytometry. Exosomal DNA was extracted in order to determine the mutational status of the EGFR and RAS genes by BEAMing Digital PCR (Sysmex). Transcriptomic analysis has been carried out from exosomal RNA through whole genome gene expression microarrays, (Affymetrix). The data was normalized by Robust Multi-Array Average (RMA) and analyzed using Transcriptome Analysis Console (TAC), MultiExperiment Viewer (MeV) software and Partek Genomics Suite. Statistical significance was established at (p ≤ 0.01).
Result
In reference to the characterization, NTA and electron microscopy showed that exosomes were obtained free of cellular debris and their size ranges from 108-125 nm, according to the size of tumor-derived microvesicles. Exosomal surface markers analyzed by immunoblot and flow cytometry were detected in samples, confirming proper isolation. Mutational analysis of EGFR and RAS genes performed on exosomal DNA shown the same pattern displayed by the origin cells. Transcriptomic analysis of the exosomal content showed that the expression of mRNAs, miRNAs and precursors were significantly different between 3D and 2D-derived exosomes. Finally, a pathway enrichment analysis was carried out to know in which biological processes (cancer-related) are involved.
Significant differential expressions were also found between mRNAs, miRNAs and pre-miRs present in exosomes from adenocarcinoma (ADC) vs. squamous cell carcinoma (SCC). Interestingly, 7 miRNAs differentially expressed in exosomes (miR-200c; miR-29a; miR-339; miR-224; miR-31; miR-21; miR-33a) had already been identified as overexpressed in tumor tissue from NSCLC patients by our group. Moreover, miR-339 y miR-21 were related to prognosis (p < 0.05) in ADC group.
Conclusion
Differences in exosomal mRNA, miRNAs and pre-miRs expression have been observed between: i) lung-tumorspheres vs. more differentiated tumor cells and ii) ADC vs. SCC cultures. In addition, the same mutational pattern was detected in exosomes as compared with their parental cultures. Therefore, exosomes can be a useful source for biomarkers analysis in NSCLC.
Supported by grant GV/2018/026, PI18/00266, & Asociación Española Contra el Cáncer (AECC Valencia).
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MA04.10 - Development and Validation of a Gene Expression-Based Prognostic Signature in Early-Stage Squamous Cell Carcinoma of the Lung (Now Available) (ID 2643)
13:30 - 15:00 | Presenting Author(s): Pinaki Bose | Author(s): Anthony Boylos, Lars Frederick Petersen, Olga Kovalchuk, Igor Kovalchuk, Michelle L Dean, Doha Itani, Karen Kopciuk, Gwyn Bebb
- Abstract
- Presentation
Background
Squamous cell carcinoma of the lung (SqCCL) accounts for about 30% of all lung cancers and is usually associated with smoking. The clinical outcomes of early stage SqCCL are heterogeneous; while 60% of Stage I and II SqCCL patients never present with recurrence after surgery, the remaining will ultimately succumb to the disease. Therefore, a robust prognostication tool is an unmet clinical need. Here, we describe the development and validation of a gene expression-based prognostic signature in Stage I and II SqCCL patients.
Method
A total of 673 primary tumour samples obtained from surgically resected Stage I and II SqCCL patients were included in this study. The Cancer Genome Atlas (TCGA) cohort contained 365 patients with gene expression data generated using RNA sequencing (RNAseq). Five data sets (GSE30219, GSE37745, GSE50081, GSE4573, GSE14814) containing 308 patients profiled using Affymetrix microarrays were obtained from the Gene Expression Omnibus (GEO) database; batch effect mitigation of gene expression data was performed using ComBat. An additional cohort of consecutive Stage I and Stage II SqCLC patients was assembled at the Tom Baker Cancer Centre (TBCC), University of Calgary and gene expression was profiled using RNAseq. We performed a two-stage development of the gene signature by performing penalized elastic net Cox regression analysis in the TCGA training cohort followed by refinement of the gene list in the compiled GEO database patients. Final validation was performed using the in-house TBCC cohort. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary outcomes of interest, respectively.
Result
All datasets used in this study were found to consist of patients with comparable clinical characteristics. A gene expression signature associated with PFS was developed in TCGA cohort that significantly stratified patients into high and low risk groups. The signature was refined in the complied GEO database cohort and validated in the U of C cohort. The signature also effectively stratified patients into high and low risk groups based on OS. We are currently performing multivariable analysis of the refined gene signature, adjusting for covariates of known prognostic value.
Conclusion
Our signature, if prospectively validated, will guide clinical decision making in SqCCL. Effective risk stratification using our signature may identify Stage I patients that will benefit from adjuvant therapy and stage II patients that could be spared adjuvant treatment following surgical resection.
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MA04.11 - Biological and Prognostic Implications of the Long Non-Coding Transcriptome in Tumour-Infiltrating Immune Cells (Now Available) (ID 2838)
13:30 - 15:00 | Presenting Author(s): Kevin W Ng | Author(s): Adam Sage, Erin A Marshall, Katey SS Enfield, Wan Lam
- Abstract
- Presentation
Background
The lung tumour microenvironment is defined by complex infiltration patterns of immune cells which can contribute to both tumour progression and rejection. The advent of targeted immunotherapies has transformed cancer therapy, leading to durable regression even in late-stage lung tumours. Single-cell RNA sequencing and deconvolution of bulk tumour samples have provided insight into the transcriptomes of tumour-infiltrating immune populations and the regulatory networks that promote cytotoxicity and exhaustion transcriptional programs. Long non-coding RNAs (lncRNAs) have emerged as master regulators of gene expression in tumour cells, but their role in immune cells remains undercharacterized. We sought to delineate lncRNA expression profiles in healthy and lung tumour-infiltrating immune cells in order to better understand transcriptional reprogramming in tumour-infiltrating immune cells and to explore their potential as biomarkers of patient outcome and response to immunotherapy.
Method
RNAseq profiles of flow-purified adaptive and innate immune subsets were analysed for lncRNA expression, yielding 4919 expressed lncRNAs. Immune lncRNAs were then mapped to tumour and paired non-malignant lung adenocarcinoma samples (TCGA n=108, BCCA n=72) and associated with infiltrating immune populations by deconvolution and methylation-based purity scores. Associations with tumour immunogenicity were assessed by somatic mutational load and expression of tumour-associated antigens. Immune-specific expression of lncRNAs was confirmed in an external single cell RNAseq dataset of lung adenocarcinomas (n=5).
Result
We found that lncRNA expression patterns display markedly greater cell-type specificity than protein-coding genes in healthy samples, supporting their role in cell-intrinsic transcriptional regulation. 323 immune lncRNAs were differentially expressed in lung tumours compared to matched non-malignant tissue, with enriched expression of immune lncRNAs in tumours with high antigenic load. Many of these genes were positively correlated with CD45 expression and negatively correlated with tumour purity, suggestive of immune cell-restricted expression patterns. Furthermore, a substantial proportion of these genes showed decreased expression in microdissected tumour samples, suggesting that immune-derived lncRNAs may account for gene expression patterns observed in bulk tumour data. We validated these findings in a scRNAseq dataset and analysed co-expression patterns of immune lncRNAs with immune cell markers in order to identify specific immune cell phenotypes and assess the interaction of immune lncRNAs with cytotoxicity and exhaustion transcriptional networks. We identify immune lncRNAs which may regulate expression of important immune genes related to NK and CD8+ T cell cytotoxicity, as well as immune lncRNAs which predict patient outcome and response.
Conclusion
We present an atlas of lncRNAs expressed in innate and adaptive immune cells, emphasizing the multifaceted roles of lncRNAs in homeostasis and anti-tumour immunity. We highlight the potential of immune infiltrate to confound differential expression analysis of bulk tumour RNAseq data, with consideration needed for tumour purity and immune infiltration levels. Our data provide a resource that will facilitate further identification of functionally and clinically useful lncRNAs.
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MA04.12 - Discussant - MA04.09, MA04.10, MA04.11 (Now Available) (ID 3732)
13:30 - 15:00 | Presenting Author(s): Alfonso Calvo
- Abstract
- Presentation
Abstract not provided
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Author of
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EP1.14 - Targeted Therapy (ID 204)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.14-39 - BRG1 Deficient Cells Are Sensitive to the Inhibition of Specific Lysine Demethylases (KDMs) in Lung Cancer (Now Available) (ID 634)
08:00 - 18:00 | Author(s): Montse Sanchez-Cespedes
- Abstract
Background
The standard treatment of non-small cell lung cancer (NSCLCs) is surgery. New therapeutics, such as tyrosine kinase inhibitors or immunotherapy may improve survival, but these treatments are only effective in small cohorts of patients. Thus, hopes of improving survival of lung cancer patients are related to the advent of novel therapeutic strategies. The classic epigenetic research focuses in the reversion of gene promoter DNA hyper methylation or histone code modifications, using a battery of unspecific drugs addressed to modify the global epigenetic code in cancer cells. In our previous work, we identified frequent inactivating mutations in the epigenetic gene BRG1 (about 20% of NSCLC), which were mutually exclusive with amplifications in the MYC oncogenic family. Unfortunately, BRG1-mutant cancer cells were also not able to respond to certain epigenetic therapies whereas cancer cells carrying MYC amplification, which are BRG1 proficient, appear to be highly sensitive to these combinations of treatments. These results show that MYC amplification could be used as a prognostic biomarker for a specific personalized therapy. In this project we observed that the mutational status of BRG1 directly correlates with the expression levels of several Lysine methyltransferases (KMTs) and Lysine demethylases (KDMs) in cancer cells. We also found that inactivating mutations in KDMs and KMTs tend to be mutually exclusive with inactivating mutations in BRG1, mutations in other SWI/SNF members and mutations in MYC oncogenic genes. Thus, we focused on targeting histone-modifying enzymes, in BRG1 proficient or deficient lung cancers cell lines.
Method
For this propose we integrate state of the art technology like genome-wide chromatin modification and transcriptome analysis, using human cell lines and preclinical models for lung cancer, including in vivo models of mice such as xenografts, subjected at different concentrations of histone deacetylase inhibitor (HDACi), lysine demethylase inhibitor (KDMi) and EZH2 inhibitor (EZH2i) to design a personalized epigenetic treatment with high efficacy and low toxicity.
Result
Our results showed that BRG1 deficient cells are not sensitive to HDACi, displaying an unexpected increase in some epigenetic marks after treatment that correlates with a global enrichment of repressive marks and EZH2 occupancy at gene promoter in BRG1-mutant cells. Otherwise, BRG1 directly regulates KDMs expression in lung cancer and demonstrates that inactivating mutations in BRG1 sensitizes cancer cells to the lysine demethylase inhibitor (KDMi). However, EZH2i seems to reverse KDMi activity in the absence of BRG1, exposing an interesting and determining role of this histone lysine methyltransferase in the sensitization of BRG1 deficient cancer cells to the KDMi.
Conclusion
The results will be of great value for the stratification of lung tumors according to their genetic or epigenetic background for tailored treatments, opening the possibility to use BRG1 mutations as a potential Biomarker for personalized epigenetic target therapy in cancer. The development of an epigenetic-based therapeutic prediction model will hopefully set the basis for future treatment of lung cancer as well as of other epithelial cancers.
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.05 - DNA-Binding and Gene Expression Profiles in Max Deficient Small Cell Lung Cancer (Now Available) (ID 377)
15:45 - 17:15 | Author(s): Montse Sanchez-Cespedes
- Abstract
- Presentation
Background
The MYC pathway is frequently altered in cancer, mostly by gene activation of the MYC-family of oncogenes (fMYC) but also by genetic inactivation of MAX, the obligate partner of MYC. While the oncogenic properties of fMYC have been extensively studied, the tumour suppressor role of MAX and the function of fMYC in MAX-mutant cells remain unclear. Further, inactivating mutations in MGA, a gene that codes for another MAX-binding partner, have been found in lung cancer. MGA is a component of the non-canonical polycomb repressive complex 1 (ncPRC1) but its precise role in lung cancer development is unknown.
Method
RNA-sequencing, chromatin immunoprecipitation and proteomic analysis were performed to identify and compare the DNA binding and gene expression profiles of MYC, MGA and MAX in MAX-restituted human small cell lung cancer (SCLC)-derived cell lines.
Result
SCLC is a high-grade neuroendocrine type of lung cancer with recurrent inactivating mutations in MAX. Recent findings have described two major SCLC subtypes based on the high expression of either ASCL1 or NEUROD1 transcription factors. According to this, ASCL1 and NEUROD1 control the expression of different set of genes which defines the two subgroups of SCLC. Here, we found that MAX-mutant SCLC cells belong to the ASCL1-transcription factor dependent group of SCLCs. In the absence of MAX, even after ectopic overexpression of MYC, there was no recruitment of MYC to the DNA. The DNA binding profile of MAX in MAX-restituted cells remained unaltered after co-overexpression of MYC, despite opposed effects in gene expression. Moreover, restitution of MAX significantly shifted the DNA occupancy of MGA, from E2F6 consensus binding sites to MYC-consensus binding sites (E-boxes). Our observations also demonstrated that ncPRC1 complex is formed regardless of the presence or absence of MAX.
Conclusion
Our data supports that MYC lacks transactivation capabilities in the absence of MAX and that the tumour suppressor role of MAX relies on its capability to counteract the gene expression triggered by its partnering with fMYC. Further, we conclude that the tumor suppressor role of MGA may be related, in part, to the regulation of E2F6 promoters.
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MS05 - Novel Biological Pathways and Druggable Targets (ID 68)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Jin Jen, Marisol Arroyo-Hernandez
- Coordinates: 9/09/2019, 11:00 - 12:30, Vancouver (2003)
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MS05.02 - Genetics Abnormalities in Chromatin Modifiers: Connection with MYC Pathway and Exploration for Therapeutics (Now Available) (ID 3462)
11:00 - 12:30 | Presenting Author(s): Montse Sanchez-Cespedes
- Abstract
- Presentation
Abstract
The understanding about the complexity of the molecular networks that regulate the epigenetic control of gene expression is boosting. Moreover, it is accepted that an abnormal function of these networks, due to genetic alterations of its components, play an essential role during tumorigenesis. Among the networks involved in this epigenetic control, there is the SWI/SNF-chromatin remodeling complex, a regulator of the accessibility of the chromatin to DNA-binding proteins (1-2). Inactivating mutations at different members of the complex have been found to be inherent to most human cancers. Our team had pioneered these investigations, being the first to report inactivating mutations at BRG1 (also SMARCA4) which codes for the ATPase of the SWI/SNF complex (3-4). In lung cancer (LC), alterations at any member of this complex affect about half of the tumors and occur in a background of wild type MYC (either C, L or N) (3). In the lasts years, inactivating mutations at other members of the complex (e.g. SNF5, PRBM, ARID1A, ARID2) have been shown to evolve in most human cancers (2,5). More recently, our laboratory also pioneered the identification of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in small cell lung cancers, where it is present in tumors that are wild type for MYC and BRG1 (6). Altogether, the genetic observations indicate the existence of an important network, involving SWI/SNF and MAX/MYC, which is critical to LC development. Using LC as a model, we have scrutinized genomic data, whole exome sequencing (WES) and RNA-sequencing, collected from patient-derived xenografts (PDXs), from patient-derived cells (PDCs) and from public databases (Sanger-COSMIC and CCLE), to delineate the gene alteration profile at epigenetic controllers (including already known drivers and novel candidates) in LC. Combined, all the alterations at epigenetic controllers include different members of the SWI/SNF complex (SMARCA4/BRG1, ARID1A, PBRM1) as well as interesting candidates such as the MAX-binding protein, MGA, or the histone-modifying enzymes (KMT2D/MLL2, KMT2G/SETD1B), among others. Some of these alterations appeared in a mutually exclusive pattern, suggesting a functional connection
We have also integrated this information to search for cancer vulnerabilities.Components of the SWI/SNF complex are known to bind to various nuclear receptors, such as those of estrogens, progesterone, androgens, glucocorticoids (GCs) and retinoic acid (RA), thereby adapting the gene expression programs to the demands of the cell environmental requirements (7-9). We found that the restitution of BRG1 in LC cells restores the gene expression signature of normal lung and that cells lacking BRG1 did not respond to RA or GCs, while restoration of BRG1 restored sensitivity (10). The co-administration of the epigenetic compounds azacitidine (demethylating agent) and SAHA (inhibitor of histone deacetylases) enhanced all these effects, both in cell cultures and in vivo, accompanied by sustained reductions in genome-wide DNA methylation. Together, these data support the notion that an inactive BRG1 confers resistance to RA and GCs, which prevents cancer cell differentiation. In contrast, the observations also indicate that RA/GC-based treatments could be designed to treat LC patients with MYC-amplified tumours. On the other hand, recent investigations have searched for vulnerabilities of BRG1-mutant cells that may be therapeutically approachable and have found that the inhibition of cyclin-dependent kinase 4/6 (CDK4/6) appear to be synthetic lethal in BRG1-deficient tumours (10). In my presentation I will be showing our last and novel observations of epigenetic-related compounds that promote cell growth inhibition specifically in BRG1-mutant lung cancers.
In parallel, gene alterations at other epigenetic-related components have also been reported in cancer. Some of these include the methyltransferase EZH2, a transcriptional repressor, the transcriptional co-activator protein p300, a histone acetyltransferase that regulates transcription via chromatin remodelling or the histone acetyltransferase CREBBP, which also acts as a scaffold to stabilize additional protein interactions with the transcription complex. In LC these alterations are more common in small cell lung cancer (SCLC). In SCLC, there is also recurrent inactivation of MAX and of MGA, proteins directly linked to the MYC trans-activation activities. Here, we found that the gene expression profile of MAX-mutant SCLC cells cluster to that of the ASCL1-transcription factor dependent group of SCLCs, which also includes NMYC- and LMYC-activated but not with MYC or BRG1-mutant SCLC cells. MGA, is an extraordinary large protein that is also recurrently inactivated in NSCLC. The MYC-MAX and MADs/MGA-MAX complexes have opposed functions in transcription, being MAX a central player in this network. MAX and MGA have shown to also act as part of the Polycomb Repression Complex 1 (PRC1), specifically the non-canonical PRC1 complex designated as ncPRC1. I will also present our data on the functional characterization of the role of MYC and of MGA in the MAX-deficient SCLC cells.
References:
1.Peterson CL et al. Five SWI/SNF gene products are components of a large multisubunit complex required for transcriptional enhancement. Proc Natl Acad Sci USA. 1994; 91: 2905-8.
2.Wilson GB, Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11: 481-92.
3.Medina PP et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mut. 2008; 29: 617-22a.
4.Rodriguez-Nieto S et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mut. 2011; 32: E1999-2017.
5.Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. Oncogene 2014; 33: 2681-9.
6. Romero OA et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov. 2014; 4: 292-303.
7. Chiba H, et al. Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucleic Acids Res. 1994; 22: 1815-182015.
8.Romero OA et al. The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med. 2012; 4: 603-16.
9. Romero OA et al. Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming. Oncogene 2017;36:1287-96.
10. Xue Y, et al.SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat Commun. 2019;10:557.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-26 - Genetic and Molecular Profiling of Non-Smoking Related Lung Adenocarcinomas (ID 1701)
09:45 - 18:00 | Author(s): Montse Sanchez-Cespedes
- Abstract
Background
The etiology and many details of the genomic profile and molecular basis of lung adenocarcinomas (LuADs) in nonsmoker patients remain elusive. Further, the scarcity of primary cultures available from non-smoking related lung adenocarcinomas (NSK-LuADs) contributes to hamper our biological understanding of these tumors.
Method
We established patient-derived cancer cell (PDCs) cultures from NSK-LuADs, and performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) analysis to delineate their genomic architecture. For validations, we analyzed independent cohorts of LuADs.
Result
The analysis revealed non-smoker related alterations such as those at the growth factor receptors RET, ALK, EGFR and ERBB2. There were also mutations affecting signal transduction molecules such as AKT1, BRAF and KRAS, and mutations in tumor suppressor genes, including TP53, CDKN2A, RB1, ARID1A, ATM and STK11. We also identified new fusions and recurrent mutations in some genes, one of them, a possible regulator of gene expression, affecting ten percent of the LuADs, thus constituting a potentially relevant tumor suppressor gene. We also report a predominance of RB1-inactivation, mostly complex intragenic rearrangements (homozygous deletions or duplications) in EGFR-mutant tumors. Three EGFR-/RB1-mutant tumors, treated with EGFR-TKIs, and one EGFR-wild type tumor, treated with standard chemotherapy, developed small cell lung cancer and/or squamous cell carcinoma transformation, evident in the re-biopsies and/or PDCs. Finally, we found pathogenic germ-line mutations at genes associated to familiar-cancer syndromes, especially the TP53-associated Li Fraumeni syndrome, affecting ten percent of EGFR-mutant LuADs patients, underscoring a genetic predisposition origin for a subset of NSK-LuADs.
Conclusion
The recurrent gene inactivation found in candidate gene in LuADs heralds a tumor suppressor role which deserves further exploration. The pre-existent inactivation of RB1 predominates in EGFR-mutant tumors and may underlie an extremely ductile nature, albeit additional gene alterations are required to overcome sensitivity to the TKIs. Given their potential clinical and therapeutic implications, testing for RB1-alterations and for the Li-Fraumeni syndrome in EGFR-mutant LuADs patients may need to be incorporated in the clinical settings.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-03 - Landscape of Gene Fusions in Lung Adenocarcinoma Patients with Minimal Cigarette Exposure Identified on Malignant Pleural Effusions (ID 575)
10:15 - 18:15 | Author(s): Montse Sanchez-Cespedes
- Abstract
Background
Gene fusions in lung adenocarcinoma (LuAD) involving tyrosine kinase receptors such as ROS1, ALK or RET are recurrent oncogenic drivers (~10%), enriched in light or never-smokers. Some of them represent emerging and predictive biomarkers for targeted therapies. Here we report the fusions detected in a cohort of metastatic LuAD patients with low tobacco exposure (never or former-smokers).
Method
Patient-derived cancer cell lines (PDC) were successfully established from malignant pleural effusions from 11 patients diagnosed with LuAD. We assessed the genetic and molecular profile by whole-exome sequencing (WES) and RNA sequencing (RNA-seq) in each cell line.
Result
Patients’ characteristics: median age, 58 (39-86); 9 were female. Eight of eleven were never-smokers and three, former-smokers. Seven patients were treatment naïve when pleural effusion samples were collected. A cytological examination of pleural fluid was performed by a lung pathologist and all samples were positive for malignant cells. Known driver mutations in lung primary tumours included one ALK translocation detected by FISH and three EGFR Del19 mutations by targeted sequencing. The three EGFR-mutant LuAD patients progressed to first or second-generation EGFR-TKI and we were able to stablish paired PDC after progressing to tyrosine kinase inhibitors (TKI) in two of them. We identified an acquired FGFR3-TACC3 fusion in one paired PDC after gefitinib progression (T790M-negative), that led to overexpression of FGFR3 concurrent with an enrichment of squamous cell lineage transcripts (e.g. TP63, SOX2) and MDM2 amplification. Among EGFR wild type (wt) patients, two RET rearrangements, CCDC6-RET and KIF5B-RET, and one EML4-ALK fusion -also detected in the primary tumour- were identified in PDC models. In addition, in two of the samples we discovered novel gene fusions that will be described in detail, involving proteins that are not kinases, and thus, their potential role in cancer is still unknown.
Conclusion
In this cohort enriched with never-smoking LuAD patients presenting pleural effusions at diagnosis, the presence of known driver fusions during the disease’s course detected by RNA-Seq was 36% (4/11), including a FGFR3-TACC3 fusion as an acquired resistance mechanism to EGFR-TKI. Further study is ongoing in our PDC models to test the functional role of these fusions in order to facilitate precision medicine.
