Lyve-1 expressing perivascular macrophages orchestrate cancer-associated fibroblast expansion to sustain angiogenesis in cancer

Tumour associated macrophages (TAMs) are a highly plastic stromal cell type which are exquisitely polarized by the tumour microenvironment (TME) to support cancer progression. We leveraged single-cell RNA-sequencing (scRNA-seq) of TAMs from a spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT) to identify three distinct polarisation trajectories for these cells within the TME. We reveal sub-divisions within the pro-tumoural TAM population with one subset expressing Lyve-1 and residing in a spatial niche proximal to blood vasculature within the tumour. We demonstrate that selective depletion of the Lyve-1+ TAM population significantly slows tumour growth because of a non-redundant role of these cells in orchestrating platelet derived growth factor-CC (PDGF-CC)-dependent expansion of aSMA+ CAF, which underpins vasculature growth and development. This study uncovers that local aSMA+ CAF expansion in cancer is not an autonomous event but tightly regulated by the perivascular Lyve-1+ TAM population, which ultimately govern the success of angiogenesis in cancer