Intertumoral Heterogeneity in SCLC Is Influenced by the Cell Type of Origin

Dian Yang, Sarah K Denny, Peyton G Greenside, Andrea C Chaikovsky, Jennifer J Brady, Youcef Ouadah, Jeffrey M Granja, Nadine S Jahchan, Jing Shan Lim, Shirley Kwok, Christina S Kong, Anna S Berghoff, Anna Schmitt, H Christian Reinhardt, Kwon-Sik Park, Matthias Preusser, Anshul Kundaje, William J Greenleaf, Julien Sage, Monte M Winslow

The extent to which early events shape tumor evolution is largely uncharacterized, even though a better understanding of these early events may help identify key vulnerabilities in advanced tumors. Here, using genetically defined mouse models of small cell lung cancer (SCLC), we uncovered distinct metastatic programs attributable to the cell type of origin. In one model, tumors gain metastatic ability through amplification of the transcription factor NFIB and a widespread increase in chromatin accessibility, whereas in the other model, tumors become metastatic in the absence of NFIB-driven chromatin alterations. Gene-expression and chromatin accessibility analyses identify distinct mechanisms as well as markers predictive of metastatic progression in both groups. Underlying the difference between the two programs was the cell type of origin of the tumors, with NFIB-independent metastases arising from mature neuroendocrine cells. Our findings underscore the importance of the identity of cell type of origin in influencing tumor evolution and metastatic mechanisms.SIGNIFICANCE: We show that SCLC can arise from different cell types of origin, which profoundly influences the eventual genetic and epigenetic changes that enable metastatic progression. Understanding intertumoral heterogeneity in SCLC, and across cancer types, may illuminate mechanisms of tumor progression and uncover how the cell type of origin affects tumor evolution. Cancer Discov; 8(10); 1-16. ©2018 AACR.See related commentary by Pozo et al., p. 1216.