Lineage plasticity in small cell lung cancer generates non- neuroendocrine cells primed for vascular mimicry
Pearsall, Sarah M Williamson, Stuart Marques, F. G. Humphrey, Sam Hughes, Ellyn Cannell, I. Frese, Kristopher K Galvin, Melanie Carter, Mathew Priest, Lynsey
Pearsall, Sarah M
Williamson, Stuart
Marques, F. G.
Humphrey, Sam
Hughes, Ellyn
Cannell, I.
Frese, Kristopher K
Galvin, Melanie
Carter, Mathew
Priest, Lynsey
Citations
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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.
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
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
Description
Date
2021
Publisher
Collections
Keywords
Type
Other
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.