Intratumoral heterogeneity generated by Notch signaling promotes small cell lung cancer

Abstract

The Notch signaling pathway mediates cell fate decisions ^{1, 2} and is tumor suppressive or oncogenic depending on the context ^{2, 3} . During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine (NE) fate ^{4– 6} . In small cell lung cancer (SCLC), an aggressive NE lung cancer ⁷ , loss-of-function NOTCH mutations and the inhibitory effects of ectopic Notch activation indicate that Notch signaling is tumor suppressive ^{8, 9} . Here, we show that Notch signaling can be both tumor suppressive and pro-tumorigenic in SCLC. Endogenous activation of the Notch pathway results in a NE to non-NE fate switch in 10-50% of tumor cells in a mouse model of SCLC and in human tumors. This switch is mediated in part by Rest/Nrsf, a transcriptional repressor that inhibits NE gene expression. Non-NE Notch-active SCLC cells are slow growing, consistent with a tumor suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to NE tumor cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumor growth and delays relapse. Thus, SCLC tumors generate their own microenvironment via activation of Notch signaling in a subset of tumor cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select SCLC patients.