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    Lineage plasticity in small cell lung cancer generates non- neuroendocrine cells primed for vascular mimicry

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    Authors
    Pearsall, Sarah M
    Williamson, Stuart
    Marques, F. G.
    Humphrey, Sam
    Hughes, Ellyn
    Cannell, I.
    Frese, Kristopher K
    Galvin, Melanie
    Carter, Mathew
    Priest, Lynsey
    Kerr, Alastair
    Humphries, M. J.
    Humphries, J. D.
    Blackhall, Fiona H
    Hannon, G.
    Sage, Julien
    Pitteri, Sharon J
    Simpson, Kathryn L
    Dive, Caroline
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    Affiliation
    Cancer Research UK Manchester Institute, Macclesfield,
    Issue Date
    2021
    
    Metadata
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    Abstract
    Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine (NE) cancer with rapid and widespread metastasis and a dismal prognosis measurable only in months. The inherent lack of tumor biopsies has limited our understanding of SCLC phenotypic heterogeneity, and except for the addition of Immune Checkpoint Inhibitors the therapeutic strategy has remained largely unchanged for decades. We are investigating Vascular Mimicry (VM) in SCLC, which is linked to poor prognosis and may provide a novel therapeutic opportunity1. VM describes the ability of aggressive tumor cells to undergo trans-endothelial differentiation, enabling angiogenesis-independent tumor vascularization. We hypothesize that, via extracellular matrix (ECM) remodeling, VM provides a favorable tumor microenvironment (TME) to support tumor progression and metastasis. We explored SCLC VM competency and molecular mechanisms underpinning this using histopathology and transcriptomic and proteomic analyses of NE and non-NE SCLC cells in patient faithful Circulating Tumor Cell (CTC)-Derived eXplant (CDX)2,3 models and genetically-engineered mouse models (GEMMs). We demonstrate that within human and murine SCLC tumors in vivo and ex vivo the non-NE cells, unlike NE cells, are VM competent. NE SCLC cells in an ASCL1-expressing CDX model undergo a Notch-driven transition to a non-NE phenotype. We show that non-NE cells are transcriptionally primed to undergo VM and express gene signatures consistent with pseudohypoxia, blood vessel development and extracellular matrix (ECM) organization. These cells undergo post-translational modification of proteins involved in cell-cell and cell-ECM adhesion including a VM-specific glycosylation of integrin β1. On Matrigel VM-primed non-NE cells remodeled the ECM forming tubular networks, an established surrogate assay for VM competence. Integrin β1 blockade impedes VM in vitro by inhibiting non-NE cell collagen adhesion and thus ECM remodeling. This previously unrecognized functional intratumoral heterogeneity in SCLC supports therapeutic co-targeting of NE and non-NE cells to curtail VM-supported tumor growth and metastasis. The ultimate aim is to identify targetable therapeutic options with which to inhibit VM to improve outcomes for patients with SCLC.
    Citation
    Pearsall SM, Williamson SC, Marqués FG, Humphrey S, Hughes E, Cannell I, et al. Abstract 2653: Lineage plasticity in small cell lung cancer generates non- neuroendocrine cells primed for vascular mimicry. In: Tumor Biology. American Association for Cancer Research; 2021.
    Journal
    Cancer Research
    URI
    http://hdl.handle.net/10541/624577
    DOI
    10.1158/1538-7445.AM2021-2653
    Additional Links
    https://dx.doi.org/10.1158/1538-7445.AM2021-2653
    Type
    Other
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1158/1538-7445.AM2021-2653
    Scopus Count
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