2. Academic Validation
  3. KDM6A epigenetically regulates subtype plasticity in small cell lung cancer

KDM6A epigenetically regulates subtype plasticity in small cell lung cancer

  • Nat Cell Biol. 2023 Aug 17. doi: 10.1038/s41556-023-01210-z.
Leslie Duplaquet # 1,  Yixiang Li # 1,  Matthew A Booker 2,  Yingtian Xie 1 3,  Sarah Naomi Olsen 4,  Radhika A Patel 5,  Deli Hong 1,  Charlie Hatton 4,  Thomas Denize 6,  Emily Walton 6,  Yasmin N Laimon 6,  Rong Li 1 3,  Yijia Jiang 1 3,  Roderick T Bronson 7,  Jackson Southard 8,  Shuqiang Li 8,  Sabina Signoretti 6 9 10,  Xintao Qiu 1 3,  Paloma Cejas 1 3,  Scott A Armstrong 4,  Henry W Long 1 3,  Michael Y Tolstorukov 2,  Michael C Haffner 5 11 12,  Matthew G Oser 13 14
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
  • 5 Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 6 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 7 Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
  • 8 Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 9 Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 10 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 11 Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 12 Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
  • 13 Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Matthew_Oser@dfci.harvard.edu.
  • 14 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, MA, USA. Matthew_Oser@dfci.harvard.edu.
  • # Contributed equally.
PMID: 37591951 DOI: 10.1038/s41556-023-01210-z
Abstract

Small cell lung Cancer (SCLC) exists broadly in four molecular subtypes: ASCL1, NEUROD1, POU2F3 and Inflammatory. Initially, SCLC subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoural subtype heterogeneity and plasticity between subtypes. Here, using a CRISPR-based autochthonous SCLC genetically engineered mouse model to study the consequences of KDM6A/UTX inactivation, we show that KDM6A inactivation induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumours that express both ASCL1 and NEUROD1. Mechanistically, KDM6A normally maintains an active chromatin state that favours the ASCL1 subtype with its loss decreasing H3K4me1 and increasing H3K27me3 at enhancers of neuroendocrine genes leading to a cell state that is primed for ASCL1-to-NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC genetically engineered mouse model to model ASCL1 and NEUROD1 subtype heterogeneity and plasticity, which is found in 35-40% of human SCLCs.

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