Abstract 2653: Lineage plasticity in small cell lung cancer generates non- neuroendocrine cells primed for vascular mimicry

Abstract

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. References 1S. C. Williamson et al., Vasculogenic mimicry in small cell lung cancer. Nat Commun 7, 1 (2016). 2C. L. Hodgkinson et al., Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nature medicine 20, 897 (2014). 3K. L. Simpson et al., A biobank of small cell lung cancer CDX models elucidates inter-and intratumoral phenotypic heterogeneity. Nature Cancer 1, 4 (2020). Citation Format: Sarah M. Pearsall, Stuart C. Williamson, Fernando García Marqués, Sam Humphrey, Ellyn Hughes, Ian Cannell, Kristopher K. Frese, Melanie Galvin, Mathew Carter, Lynsey Priest, Alastair Kerr, Martin J. Humphries, Jonathon D. Humphries, Fiona Blackhall, Gregory Hannon, Julien Sage, Sharon J. Pitteri, Kathryn L. Simpson, Caroline Dive. Lineage plasticity in small cell lung cancer generates non- neuroendocrine cells primed for vascular mimicry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2653.