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Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models.
Lissa, Delphine; Takahashi, Nobuyuki; Desai, Parth; Manukyan, Irena; Schultz, Christopher W; Rajapakse, Vinodh; Velez, Moises J; Mulford, Deborah; Roper, Nitin; Nichols, Samantha; Vilimas, Rasa; Sciuto, Linda; Chen, Yuanbin; Guha, Udayan; Rajan, Arun; Atkinson, Devon; El Meskini, Rajaa; Weaver Ohler, Zoe; Thomas, Anish.
Affiliation
  • Lissa D; Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Takahashi N; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Desai P; Medical Oncology Department, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.
  • Manukyan I; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Schultz CW; Laboratory of Pathology, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Rajapakse V; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Velez MJ; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Mulford D; Department of Pathology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Roper N; Department of Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • Nichols S; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Vilimas R; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Sciuto L; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Chen Y; Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Guha U; Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA.
  • Rajan A; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • Atkinson D; Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, Bethesda, MD, 20892, USA.
  • El Meskini R; Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
  • Weaver Ohler Z; Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
  • Thomas A; Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
Nat Commun ; 13(1): 2023, 2022 04 19.
Article in En | MEDLINE | ID: mdl-35440132
ABSTRACT
Molecular subtypes of small cell lung cancer (SCLC) defined by the expression of key transcription regulators have recently been proposed in cell lines and limited number of primary tumors. The clinical and biological implications of neuroendocrine (NE) subtypes in metastatic SCLC, and the extent to which they vary within and between patient tumors and in patient-derived models is not known. We integrate histology, transcriptome, exome, and treatment outcomes of SCLC from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of NE differentiation. Transcriptomic analysis confirms previously described subtypes based on ASCL1, NEUROD1, POU2F3, YAP1, and ATOH1 expression, and reveal a clinical subtype with hybrid NE and non-NE phenotypes, marked by chemotherapy-resistance and exceedingly poor outcomes. NE tumors are more likely to have RB1, NOTCH, and chromatin modifier gene mutations, upregulation of DNA damage response genes, and are more likely to respond to replication stress targeted therapies. In contrast, patients preferentially benefited from immunotherapy if their tumors were non-NE. Transcriptional phenotypes strongly skew towards the NE state in patient-derived model systems, an observation that was confirmed in paired patient-matched tumors and xenografts. We provide a framework that unifies transcriptomic and genomic dimensions of metastatic SCLC. The marked differences in transcriptional diversity between patient tumors and model systems are likely to have implications in development of novel therapeutic agents.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neuroendocrine Tumors / Small Cell Lung Carcinoma / Lung Neoplasms Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Neuroendocrine Tumors / Small Cell Lung Carcinoma / Lung Neoplasms Type of study: Prognostic_studies Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2022 Document type: Article Affiliation country: United States
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