In a new article published in Cancer Cell, a subset of cancer-associated fibroblasts (CAFs) was shown to have a crucial role in promoting lymphovascular invasion (LVI) in early-stage bladder cancer.

In this study, LVI analysis in tissue samples from patients with bladder cancer showed that LVI in patients with early-stage disease was associated with increased rates of lymph node (LN) metastases and poor prognosis. Single-cell RNA sequencing analyses showed an enrichment of PDGFRα+ITGA11+ CAFs specifically in patients with LVI-positive early-stage bladder cancer. The presence of this CAF subpopulation was associated with poor prognosis and LVI. Conditional knockout of PDGFRα+ITGA11+ CAFs in a mouse model of bladder cancer substantially reduced LVI and LN metastases, suggesting that this CAF population has a crucial role in LVI. Mechanistically, PDGFRα+ITGA11+ CAFs were shown to attach to human lymphatic endothelial cells (HLECs) in vitro in an ITGA11-dependent manner, as this attachment was impaired in the absence of ITGA11. The surface receptor SELE was identified as the strongest ITGA11 binding partner on HLECs, and an increased ITGA11–SELE interaction was observed in tissue samples from patients with LVI-positive versus LVI-negative early-stage bladder cancer. SELE was required for PDGFRα+ITGA11+ CAF migration and attachment to HLECs. Moreover, transendothelial migration of bladder cancer cells in vitro decreased upon genetic knockdown of SELE or ITGA11. Mechanistically, the ITGA11–SELE interaction was shown to promote VEGFR3 phosphorylation and subsequent MAPK pathway activation in HLECs, which in turn promoted transendothelial migration of bladder cancer cells. The evidence that the activation of VEGFR–MAPK per se was not sufficient to promote bladder cancer LVI and LN metastasis prompted the authors to investigate the existence of additional mechanisms mediated by other factors on PDGFRα+ITGA11+ CAFs. An upregulation of extracellular matrix (ECM) remodelling genes was observed in PDGFRα+ITGA11+ CAFs, and this ECM remodelling was shown to increase bladder cancer cell spheroid migration through overexpression of the ECM remodelling cytokine CHI3L1.