A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity

Kathryn L. Simpson, Ruth Stoney, Kristopher K. Frese, Nicole Simms, William Rowe, Simon P. Pearce, Sam Humphrey, Laura Booth, Derrick Morgan, Marek Dynowski, Francesca Trapani, Alessia Catozzi, Mitchell Revill, Thomas Helps, Melanie Galvin, Luc Girard, Daisuke Nonaka, Louise Carter, Matthew G. Krebs, Natalie CookMathew Carter, Lynsey Priest, Alastair Kerr, Adi F Gazdar, Fiona Blackhall, Caroline Dive

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined by neuroendocrine transcription factor (NETF) expression. Circulating-tumor-cell-derived explant models (CDX) recapitulate donor patients' tumor morphology, diagnostic NE marker expression and chemotherapy responses. We describe a biobank of 38 CDX models, including six CDX pairs generated pretreatment and at disease progression revealing complex intra- and intertumoral heterogeneity. Transcriptomic analysis confirmed three of four previously described subtypes based on ASCL1, NEUROD1 and POU2F3 expression and identified a previously unreported subtype based on another NETF, ATOH1. We document evolution during disease progression exemplified by altered MYC and NOTCH gene expression, increased 'variant' cell morphology, and metastasis without strong evidence of epithelial to mesenchymal transition. This CDX biobank provides a research resource to facilitate SCLC personalized medicine.

Original languageEnglish (US)
Pages (from-to)437-451
Number of pages15
JournalNature Cancer
Volume1
Issue number4
DOIs
StatePublished - Apr 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity'. Together they form a unique fingerprint.

Cite this