Suchergebnisse

Although it is well established that tumor-associated macrophages take part in each step of cancer progression, less is known about the distinct role of the so-called metastasis-associated macrophages (MAMs) at the metastatic site. Previous studies reported that Caveolin-1 (Cav1) has both tumor-promoting and tumor-suppressive functions. However, the role of Cav1 in bone-marrow-derived cells is unknown. Here, we describe Cav1 as an anti-metastatic regulator in mouse models of lung and breast cancer pulmonary metastasis. Among all the recruited inflammatory cell populations, we show that MAMs uniquely express abundant levels of Cav1. Using clodronate depletion of macrophages, we demonstrate that macrophage Cav1 signaling is critical for metastasis and not for primary tumor growth. In particular, Cav1 inhibition does not affect MAM recruitment to the metastatic site but, in turn, favors angiogenesis. We describe a mechanism by which Cav1 in MAMs specifically restrains vascular endothelial growth factor A/vascular endothelial growth factor receptor 1 (VEGF-A/VEGFR1) signaling and its downstream effectors, matrix metallopeptidase 9 (MMP9) and colony-stimulating factor 1 (CSF1). ; FWO-Strategic Basic Research (SB) doctoral fellowship (1S26917N), G.D.C. by a Pegasus FWO-Marie Curie fellowship (12114113N), A.I.O. by FCT Portugal (SFRH/BD/52287/2013), and M.E. by the DFG (EH 472/1-1) and Kom op tegen Kanker (Stand up to Cancer), the Flemish cancer society (2016/10538/2453). B.M.C. was funded by FCT Portugal (IF/00601/2012). M.M. received an ERC starting grant (OxyMO, 308459) and long-term structural Methusalem funding by the Flemish government (METH.14.08) ...

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