Abstract IA12: Intra- and intertumoral heterogeneity and response to therapy in mouse models of SCLC

Abstract

Abstract Small cell lung cancer (SCLC) is a high-grade neuroendocrine carcinoma that accounts for ~15% of all lung cancers and causes over 200,000 deaths worldwide each year. The majority of SCLC patients have metastatic disease at the time of diagnosis; for these patients, the median survival, even with treatment, is 7-12 months, and the 5-year overall survival is <1%. SCLC is managed with first-line chemotherapy–often cisplatin or carboplatin with etoposide. However, the majority of SCLC patients suffer relapse within months of completing initial therapy due to the persistence of a subpopulation of chemotherapy-resistant cells. Treatment options for SCLC have remained virtually unchanged for the past 30 years, and there are no approved targeted therapies in SCLC. To dissect the molecular changes that regulate SCLC progression, it is critical to analyze purified SCLC cells from tumors at known stages of tumorigenesis. This has not been possible previously using either mouse models or human specimens due to the 1) limited access to lung cancers at defined stages of malignant progression, 2) inability to unambiguously isolate SCLC cells away from stromal cells, and 3) difficulty in performing genome-wide analyses on the few cells that can be isolated from metastases in mouse models or patient biopsies. To overcome these obstacles, we have developed mouse models of SCLC including Cre/lox-mediated deletion of key tumor suppressors (p53, Rb, and the Rb family member p130) as well as activation of fluorescent reporters. This triple-knockout (TKO) model recapitulates the genetics, histology, and metastatic ability of human SCLC. Using this mouse model, we have recently identified new levels of intratumoral heterogeneity in SCLC tumors, including the presence of tumor-propagating cells (TPCs) as well as Notch-active non-neuroendocrine tumor cell population that promotes the growth of TPCs in a non-cell autonomous but tumor-intrinsic manner. Using TKO mice, we have also uncovered distinct mechanisms of intertumoral heterogeneity during tumor progression; in particular, we have shown that one group of tumors gains metastatic potential by upregulation of the Nfib transcription factor and extensive changes in their chromatin state, while others become metastatic in absence of Nfib-driven chromatin dynamics. These observations will be discussed in the context of how SCLC tumors respond to chemotherapy and candidate targeted therapies. Citation Format: Jing Shan Lim, Dian Yang, Yan Ting Shue, Monte Winslow, Julien Sage. Intra- and intertumoral heterogeneity and response to therapy in mouse models of SCLC [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA12.