Plasticity in the Absence of NOTCH Uncovers a RUNX2-Dependent Pathway in Small Cell Lung Cancer.

Neuroendocrine to non-neuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20-25% of SCLCs harbor loss of function (LOF) NOTCH mutations. Previous studies demonstrated that NOTCH functions as a SCLC tumor suppressor, but can also drive non-neuroendocrine plasticity to support SCLC growth. Given the dual functionality of NOTCH, it's not understood why SCLCs select for LOF NOTCH mutations and how these mutations impact SCLC tumorigenesis. In a CRISPR-based genetically-engineered mouse model of SCLC, genetic loss of Notch1 or Notch2 modestly accelerated SCLC tumorigenesis. Interestingly, Notch-mutant SCLCs still formed non-neuroendocrine subpopulations, and these Notch-independent, non-neuroendocrine subpopulations were driven by Runx2-mediated regulation of Rest. Notch2-mutant non-neuroendocrine cells highly express innate immune signaling genes including STING and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote non-neuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations.