TCF21high pericyte subpopulation promotes cancer metastasis by remodeling perivascular matrix

The role of perivascular cell heterogeneity in tumor metastasis remains unknown. Here, we dissected the heterogeneity of perivascular cells by single-cell RNA sequencing and defined 13 subpopulations of pericytes within human colorectal cancers (CRC). Among them, an extracellular matrix (ECM)-rich subpopulation of TCF21high tumor pericytes (TPCs) was identified, which highly correlated with metastatic potentials in human CRC patients. Pericyte-specific conditional deletion of Tcf21 in mice mitigated CRC metastasis by decreasing perivascular ECM resmodeling, maintaining the integrity of the basement membrane, and reducing circulating cancer cells. Conversely, co-injection of CRC cells with TCF21high TPCs markedly promoted metastasis. Mechanistically, high expression of TCF21 in TPCs altered ECM stiffness, collagen deposition/rearrangement, and basement membrane degradation, which collectively instigated tumor cell intravasation and metastasis. Compelling experimental evidence showed that the loss of integrin a5 activated the FAK/PI3K/AKT axis, impaired DNA hypermethylation of TCF21, leading to high expression of TCF21 in TPCs. Our data provide new mechanistic insights into functions of a specific subpopulation of perivascular cells in promoting cancer metastasis and therapeutic targeting of metastasis-promoting TPCs may provide a new paradigm for cancer therapy. Overall design: Colon cancer vascular pericytes--CCVC-1 (lymphatic metastasis), colon cancer perivascular cells--PCCVC-1 (lymphatic metastasis), rectal cancer vascular pericytes--RCVC-1 (non-metastasized), rectal cancer perivascular cells Pericytes--PRCVC-1 (non-metastatic), sigmoid colon cancer vascular pericytes--CCVC-2 (liver metastasis), parasigmoid vascular pericytes--PCCVC-2 (liver metastasis), 3 human cancer tissues and cancer cells beside of (six tissues combined) 10x single-cell sequencing