Abstract A37: Tumor heterogeneity in SCLC: A role for endogenous Notch signaling

Small cell lung cancer (SCLC), a very aggressive neuroendocrine (NE) tumor of the lung, constitutes approximately 15% of all lung cancers and has a 5-year survival rate of only 5%. Resistance following initial chemotherapy and radiation treatments accounts for the high rate of recurrence and the overall poor prognosis of SCLC. Through genomic sequencing of 100 human SCLC tumors, the group of Roman Thomas and Martin Peifer identified universal inactivation of RB and p53 and inactivating mutations in the NOTCH receptors in ~25% of the tumors. Accordingly, we found that activation of the Notch pathway in a pre-clinical mouse model for SCLC dramatically reduces the number of tumors and extends the survival of the mice. Acute Notch activation also inhibits NE gene expression and proliferation in SCLC tumor cells, providing further evidence for a tumor suppressive role for Notch in SCLC (George, Lim, et al., Nature, 2015). Intriguingly, however, we recently identified a population of cells in mouse and human SCLC tumors that exhibit endogenous activation of the Notch pathway. This observation raises the question of why tumor cells would activate a tumor suppressive pathway. Consistent with the inhibitory role of the pathway in NE differentiation, these Notch-active SCLC cells comprise a slow-cycling, non-NE compartment within SCLC tumors. Lineage tracing experiments indicate that NE tumor cells generate these non-NE Notch-active cells during tumorigenesis. Importantly, our data suggest that these slow-growing Notch-active SCLC cells may function as tumor-derived stromal-like cells that confer a growth or protective advantage to the NE tumor cells under certain growth conditions. In conclusion, Notch is a potent suppressor of SCLC. However, Notch may have pro-tumorigenic effects in SCLC, possibly under stress conditions. A better understanding of the molecular and cellular roles of Notch is required before therapeutic strategies manipulating the Notch pathway can be used in SCLC patients. Citation Format: Jing Shan Lim, Alvaro Ibaseta, Dian Yang, Nadine S. Jahchan, Julien Sage. Tumor heterogeneity in SCLC: A role for endogenous Notch signaling. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A37.