Journal
CANCER RESEARCH
Volume 82, Issue 2, Pages 248-263Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-1991
Keywords
-
Categories
Funding
- William Raveis Charitable Fund Clinical Investigator of the Damon Runyon Cancer Research Foundation [CI-101-19]
- NCI/NIH K08 grant [K08CA222657]
- Kaplan Family Fund
- DF/HCC Lung Cancer Program
- Gross-Loh research fellowship
- NCI [NIH 5 P30 CA06516]
Ask authors/readers for more resources
The study reveals the role of NOTCH mutations in small cell lung cancer (SCLC) tumorigenesis and plasticity. The loss-of-function NOTCH mutations in SCLCs can drive nonneuroendocrine plasticity and promote tumor growth. The study also identifies a Notch-independent mechanism involving RUNX2-REST pathway and innate immune signaling, which suggests potential therapeutic approaches for SCLCs with NOTCH2 mutations.
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. Significance: A genetically engineered mouse model of NOTCH-mutant SCLC reveals that nonneuroendocrine plasticity persists in the absence of NOTCH, driven by a RUNX2-REST-dependent pathway and innate immune signaling.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available