Tumor vessel co-option probed by single-cell analysis
Tumor vessel co-option is poorly understood, yet it is a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer and myeloid cells in tumors growing via vessel co-option, has not been investigated at the single-cell level. Here, we use a murine AAT-resistant lung tumor model, in which VEGF-targeting induces vessel co-option for continued growth. Single-cell RNA sequencing (scRNA-seq) of 31,964 cells reveals, unexpectedly, a largely similar transcriptome of co-opted tumor ECs (TECs) and pericytes as their healthy counterparts. Notably, we identify cell types that might contribute to vessel co-option, i.e., an invasive cancer-cell subtype, possibly assisted by a matrix-remodeling macrophage population, and another M1-like macrophage subtype, possibly involved in keeping or rendering vascular cells quiescent. ; L.-A.T., L.D., S.V.L., and P.V. are supported by Fonds Oncologie Augustinus-Koning Boudewijnstichting and GZA Ziekenhuizen; A.C., K.R., N.V.C., L.P.M.H.d.R., and L.T. by the Fonds Wetenschappelijk Onderzoek (FWO); S.J.D. by a Marie Curie-IEF fellowship; V.G. by Strategisch Basisonderzoek FWO (SB-FWO); Y.L. by BGI-Research, Danish Research Council for Independent Research (DFF-1337-00128), Sapere Aude Young Research Talent Prize (DFF-1335–00763A), and Aarhus University Strategic Grant (AU-iCRISPR); and P.C. by Methusalem funding (Flemish government), Fund for Scientific Research-Flanders (FWO-Vlaanderen), Foundation Against Cancer (2016-078), Kom op tegen Kanker (Stand up to Cancer, Flemish Cancer Society), European Research Council (ERC Proof of Concept grant ERC-713758 and Advanced ERC Research grant EU-ERC743074), and a NNF Laureate Research Grant from Novo Nordisk Foundation (NNF19OC0055802). ; Yes