Start Your Search
MS 07 - SCLC Biology & Models (ID 25)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
MS07.02 - GEM Models (p53/Rb) (ID 1873)
14:15 - 15:45 | Author(s): K. Sutherland
Small cell lung cancer (SCLC) is an aggressive neuroendocrine (NE) tumour associated with poor 5-year survival rates. Given the difficulties associated with obtaining human material, genetically engineered mouse models (GEMMs) for SCLC have emerged as powerful pre-clinical tools for translational research. Inactivation of the tumour suppressor genes TRP53 and RB1 is almost universally found in human SCLC. Based on this observation, the Berns Laboratory generated a mouse model of sporadic SCLC whereby p53 and Rb1 loss was restricted to lung epithelial cells by intra-tracheal instillation of an Adeno-Cre virus (Cre expression is under the control of a ubiquitous CMV promoter). These mice develop NE lung tumours with striking morphological and genomic similarities to SCLC observed in human patients. This model allows us to address questions that would not be possible using patient samples or cancer cell lines alone. In my presentation, I will provide an overview on the GEMMs for SCLC currently available. I will also touch upon the emergence of new gene editing technologies, such as CRISPR-Cas9, and how these techniques can be used to further manipulate current models to address clinically relevant questions. Lung cancers exhibit a high level of intra-tumoral heterogeneity. The histopathology of individual tumour subtypes, suggests that these tumours have distinct cells-of-origin, but this has not been formally shown. I will present the work we carried out to address the cellular origins of lung cancer, with a focus on the research we performed using the GEMM of SCLC (p53[f/f];Rb1[f/f]). Briefly, we generated a series of recombinant adenoviruses that target Cre-recombinase expression selectively in Club (Ad5-CC10-Cre), alveolar type 2 (Ad5-SPC-Cre) and neuroendocrine (Ad5-CGRP-Cre) cells. To address the cellular origins of SCLC, we infected p53[f/f];Rb1[f/f] mice with our cell type-restricted Adeno-Cre viruses, listed above. Results from these studies show that inactivation of p53 and Rb1 can efficiently transform neuroendocrine (CGRP-positive) and to a lesser extent, alveolar type 2 (SPC-positive) cells leading to SCLC. In contrast, CC10-expressing cells were largely resistant to transformation. The results clearly indicate that neuroendocrine cells serve as the predominant cell-of-origin of SCLC. Interestingly genome-sequencing studies have revealed genetic aberrations that overlap with squamous cell carcinomas in a subset of SCLCs. Does this reflect a common cellular origin? I will present some recent data we have generated to address this question. References 1. Meuwissen R, Linn SC, Linnoila RI, Zevenhoven J, Mooi WJ and Berns A. Induction of small cell lung cancer by somatic inactivation of both Trp53 and Rb1 in a conditional mouse model. Cancer Cell 2003 vol. 4(3) pp. 181-189. 2. Sutherland KD, Proost N, Brouns I, Adriaesen D, Song J-Y and Berns A. Cell of origin in small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of the adult mouse lung. Cancer Cell 2011 vol. 19(6) pp. 754-764.
Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.