Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models

Delphine Lissa, Nobuyuki Takahashi, Parth Desai, Irena Manukyan, Christopher W. Schultz, Vinodh Rajapakse, Moises J. Velez, Deborah Mulford, Nitin Roper, Samantha Nichols, Rasa Vilimas, Linda Sciuto, Yuanbin Chen, Udayan Guha, Arun Rajan, Devon Atkinson, Rajaa El Meskini, Zoe Weaver Ohler and Anish Thomas ()
Additional contact information
Delphine Lissa: Center for Cancer Research, NCI
Nobuyuki Takahashi: Center for Cancer Research, NCI
Parth Desai: Center for Cancer Research, NCI
Irena Manukyan: Center for Cancer Research, NCI
Christopher W. Schultz: Center for Cancer Research, NCI
Vinodh Rajapakse: Center for Cancer Research, NCI
Moises J. Velez: University of Rochester Medical Center
Deborah Mulford: University of Rochester Medical Center
Nitin Roper: Center for Cancer Research, NCI
Samantha Nichols: Center for Cancer Research, NCI
Rasa Vilimas: Center for Cancer Research, NCI
Linda Sciuto: Center for Cancer Research, NCI
Yuanbin Chen: Cancer and Hematology Centers of Western Michigan
Udayan Guha: Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI
Arun Rajan: Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI
Devon Atkinson: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research
Rajaa El Meskini: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research
Zoe Weaver Ohler: Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research
Anish Thomas: Center for Cancer Research, NCI

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29517-9

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