Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry

Sarah M Pearsall, Stuart C Williamson, Sam Humphrey, Ellyn Hughes, Derrick Morgan, Fernando J García Marqués, Griselda Awanis, Rebecca Carroll, Laura Burks, Yan Ting Shue, Abel Bermudez, Kristopher K Frese, Melanie Galvin, Mathew Carter, Lynsey Priest, Alastair Kerr, Cong Zhou, Trudy G Oliver, Jonathan D Humphries, Martin J HumphriesFiona Blackhall, Ian G Cannell, Sharon J Pitteri, Gregory J Hannon, Julien Sage, Caroline Dive, Kathryn L Simpson

Research output: Contribution to journalArticlepeer-review


INTRODUCTION: Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including SCLC. In genetically engineered mouse models (GEMMs) of SCLC, NOTCH, and MYC co-operate to drive a neuroendocrine (NE) to non-NE phenotypic switch, and co-operation between NE and non-NE cells is required for metastasis. Here, we define the phenotype of VM-competent cells and molecular mechanisms underpinning SCLC VM using circulating tumor cell-derived explant (CDX) models and GEMMs.

METHODS: We analyzed perfusion within VM vessels and their association with NE and non-NE phenotypes using multiplex immunohistochemistry in CDX, GEMMs, and patient biopsies. We evaluated their three-dimensional structure and defined collagen-integrin interactions.

RESULTS: We found that VM vessels are present in 23/25 CDX models, 2 GEMMs, and in 20 patient biopsies of SCLC. Perfused VM vessels support tumor growth and only NOTCH-active non-NE cells are VM-competent in vivo and ex vivo, expressing pseudohypoxia, blood vessel development, and extracellular matrix organization signatures. On Matrigel, VM-primed non-NE cells remodel extracellular matrix into hollow tubules in an integrin β1-dependent process.

CONCLUSIONS: We identified VM as an exemplar of functional heterogeneity and plasticity in SCLC and these findings take considerable steps toward understanding the molecular events that enable VM. These results support therapeutic co-targeting of both NE and non-NE cells to curtail SCLC progression and to improve the outcomes of patients with SCLC in the future.

Original languageEnglish
Pages (from-to)1362-1385
Number of pages24
JournalJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
Issue number10
Publication statusPublished - Oct 2023


  • Animals
  • Mice
  • Humans
  • Lung Neoplasms/pathology
  • Neovascularization, Pathologic/genetics
  • Cell Transdifferentiation
  • Cell Line, Tumor


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