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

Deli Hong, Erik H. Knelson, Yixiang Li, Yavuz T. Durmaz, Wenhua Gao, Emily Walton, Amir Vajdi, Tran Thai, Maura Sticco-Ivins, Amin H. Sabet, Kristen L. Jones, Anna C. Schinzel, Rod T. Bronson, Quang De Nguyen, Michael Y. Tolstorukov, Marina Vivero, Sabina Signoretti, David A. Barbie, Matthew G. Oser

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Neuroendocrine to nonneuroendocrine plasticity supports small cell lung cancer (SCLC) tumorigenesis and promotes immunogenicity. Approximately 20% to 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 nonneuroendocrine plasticity to support SCLC growth. Given the dual functionality of NOTCH, it is not understood why SCLCs select for LOF NOTCH mutations and how these mutations affect 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 nonneuroendocrine subpopulations, and these Notch-independent, nonneuroendocrine subpopulations were driven by Runx2-mediated regulation of Rest. Notch2-mutant nonneuroendocrine cells highly express innate immune signaling genes including stimulator of interferon genes (STING) and were sensitive to STING agonists. This work identifies a Notch-independent mechanism to promote nonneuroendocrine plasticity and suggests that therapeutic approaches to activate STING could be selectively beneficial for SCLCs with NOTCH2 mutations.

Original languageEnglish
Pages (from-to)248-263
Number of pages16
JournalCancer Research
Volume82
Issue number2
DOIs
StatePublished - 15 Jan 2022
Externally publishedYes

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