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Alvaro Andrades
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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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MA17.06 - Plakophilin 1 Enhances MYC Expression, Promoting Squamous Cell Lung Cancer (Now Available) (ID 823)
15:45 - 17:15 | Author(s): Alvaro Andrades
- Abstract
- Presentation
Background
Plakophilin 1 (PKP1) is a member of the arm-repeat (armadillo) and plakophilin gene families, being an important component of the desmosome. Although desmosomes loss-of-function has been associated with increased cell migration and pro-oncogenic activity, we have observed consistent PKP1 overexpression in patient samples of squamous cell lung cancer (SqCLC) in comparison with lung adenocarcinoma (LUAD) and non-tumoral controls from two datasets achieved by our group, and also from three additional independent datasets.
Method
In order to explore this paradox, we developed in vitro and in vivo PKP1 gain/loss functional models in SqCLC cell lines and also we challenged our hypothesis in some LUAD cell lines.
Result
Greater cell dissemination but reduced cell proliferation was observed in CRISPR-Cas9 induced, PKP1-knockout clones. Furthermore, PKP1 expression promoted cell proliferation, cell survival, and in vivo xenograft engraftment.
Interestingly, we demonstrated through several functional experiments (chromatin immunoprecipitation, RNA immunoprecipitation, direct mutagenesis combined with luciferase assays, Western blot, qPCR... among others), and in 7 cell lines from different lung cancer subtypes (5 SqCLC and 2 LUAD cell lines), and different contexts (with and without PKP1 basal expression in order to set up gain and loss expression assays), that these pro-oncogenic activities were mediated by the functional direct relationship between PKP1 and the oncogene MYC. Specifically, PKP1 enhances MYC translation, and MYC increases PKP1 transcription, linking both proteins in a positive feedforward loop.
Conclusion
These observations provide a new molecular mechanism of cancer development, revealing PKP1 as a novel oncogene in SqCLC, and as an effective post-transcriptional regulator of MYC, which has been described as overexpressed in around 70% of NSCLC tumors.
Moreover, PKP1 unveiled as a valuable diagnostic biomarker and a potential therapeutic target for SqCLC. Importantly, PKP1 inhibition may open up the possibility of indirectly targeting MYC, not only in NSCLC (where, as mentioned before, is frequently overexpressed), but also in other tumors. This is of particular interest, because MYC is an oncogene that is dysregulated in most human cancers and is acknowledged as a “most wanted” target for cancer therapy.
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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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P1.03-20 - Exploring Driver Mutations in Non-Coding RNAs in Lung Adenocarcinoma (ID 1686)
09:45 - 18:00 | Presenting Author(s): Alvaro Andrades
- Abstract
Background
Lung adenocarcinoma (LUAD) is the most frequent subtype of lung cancer, which is the leading cause of cancer death worldwide. Unraveling the molecular mechanisms of LUAD is crucial for identifying novel biomarkers and molecular targets for the diagnosis, prognosis and treatment of LUAD. One of the main molecular mechanisms responsible for LUAD and other cancers is the accumulation of driver somatic mutations, which undergo positive selection. However, driver mutations only represent a small proportion of the total mutations in a tumor and identifying true drivers can be challenging, especially in non-coding regions.
Non-coding RNAs are RNA molecules that do not code for protein. Increasing evidence suggests that many non-coding RNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play critical roles in most, if not all hallmarks of cancer. However, very little is known about the driver mutations that affect non-coding RNAs in cancer and, in particular, in lung adenocarcinoma (LUAD).
Method
We performed targeted next-generation sequencing on genomic DNA from 70 LUAD primary tumors, focusing on 1470 miRNAs and 913 lncRNAs. We developed a novel bioinformatics pipeline to identify somatic mutations by combining three state-of-the-art mutation calling tools, and then we prioritized the high-confidence somatic mutations based on various published functional impact metrics specifically designed for miRNAs and for lncRNAs. In addition, we further validated our pipeline and our results using whole-genome sequencing data from 59 LUAD primary tumors from The Cancer Genome Atlas (TCGA).
Result
We identified 193 miRNA mutations in our cohort of 70 LUAD primary tumors. These included 16 mutations affecting seed regions and 48 mutations affecting mature miRNAs. Using miRNA target prediction tools, we identified one somatic mutation that affected the seed of a well-known miRNA and that significantly altered the predicted targets of the miRNA. In lncRNAs, we found 2004 mutations in out cohort, out of which 565 passed preliminary filters based on the predicted functional impact. Of those mutations, 91 were recurrent in more than one patient, and some affected well-known lncRNAs such as HOTAIR and PVT1. The results from our internal cohort differed greatly from those obtained from TCGA patients. Future work will focus on refining the mutation prioritization pipeline and experimentally validating the most significant results.
Conclusion
Our novel pipeline may aid in the identification of novel driver mutations in non-coding RNAs, which may reveal novel biomarkers and molecular targets for the diagnosis, prognosis and treatment of LUAD.
