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Plasticity in the Absence of NOTCH Uncovers a RUNX2-Dependent Pathway in Small Cell Lung Cancer.
Hong, Deli; Knelson, Erik H; Li, Yixiang; Durmaz, Yavuz T; Gao, Wenhua; Walton, Emily; Vajdi, Amir; Thai, Tran; Sticco-Ivins, Maura; Sabet, Amin H; Jones, Kristen L; Schinzel, Anna C; Bronson, Rod T; Nguyen, Quang-De; Tolstorukov, Michael Y; Vivero, Marina; Signoretti, Sabina; Barbie, David A; Oser, Matthew G.
Afiliação
  • Hong D; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Knelson EH; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Li Y; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Durmaz YT; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Gao W; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Walton E; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Vajdi A; Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Thai T; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Sticco-Ivins M; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Sabet AH; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Jones KL; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Schinzel AC; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Bronson RT; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts.
  • Nguyen QD; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Tolstorukov MY; Department of Informatics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Vivero M; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Signoretti S; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Barbie DA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Oser MG; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Cancer Res ; 82(2): 248-263, 2022 01 15.
Article em En | MEDLINE | ID: mdl-34810201
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Receptor Notch1 / Receptor Notch2 / Subunidade alfa 1 de Fator de Ligação ao Core / Carcinoma de Pequenas Células do Pulmão / Plasticidade Celular / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Receptor Notch1 / Receptor Notch2 / Subunidade alfa 1 de Fator de Ligação ao Core / Carcinoma de Pequenas Células do Pulmão / Plasticidade Celular / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article