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

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. 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.

RUNX2 facilitates aggressiveness and chemoresistance of triple negative breast cancer cells via activating MMP1

“…Therefore, despite chemotherapy serve as the “one size fits all” approach, yet the current treatment paradigm for TNBC administration is challenging and inopportune largely due to the deficiency of dissecting the clinical response and underlying molecular characteristics. Of note, state-of-the-art renewal has indicated the oncogenic role of RUNX2 in multiple cancer types ( 16 – 18 ), which the expression pattern and regulatory mechanism during chemoresistance in triple negative breast cancer are largely indistinct. For the purpose, we verified that RUNX2 knockdown was adequate to inhibit the in vitro proliferation, migration, invasion, and chemoresistance of resistant cells in triple negative breast cancer as well as the tumor growth in BALB/c nude mice.…”

DLL3 regulates Notch signaling in small cell lung cancer

“…In future studies, it will be interesting to examine the exact nature of the NCAM low ICAM low population in RPR2;Rosa26 Dll3 tumors, such as whether these cells represent a precursor cell similar to lung epithelial cells during early lung development before Notch signaling is activated or another population of non-NE cells that do not require Notch. 51 Our new mouse allele for DLL3 expression may also be useful in the future to investigate how DLL3 plays Notch-dependent and Notch-independent roles both in developmental processes and in cancer.…”

Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions

“…Second, although long appreciated (16,17), variation in the degree of 2 of 20 NE differentiation in SCLC has recently been explored more carefully (18)(19)(20). REST is a repressor of neuronal cell fate that is variably active in SCLC, with REST-active SCLC exhibiting a suppressed NE gene expression profile (14,21,22). In addition, recent large-scale immunohistochemistry (IHC) analyses have established that ASCL1 and NEUROD1 are coexpressed in a substantial fraction of tumors (23)(24)(25)(26), and a double-positive (ASCL1 + NEUROD1) subtype has also been proposed on the basis of bulk transcriptomic analysis of SCLC patient-derived xenograft (PDX) models (27).…”