Dudley, A. C. | bioRxiv Science

bioRxiv2022

Melanoma cells appropriate pericyte:endothelial cell crosstalk during perivascular invasion in the brain

Post brain colonization, cancer cells may adhere to and spread along the abluminal surface of the vasculature providing advantageous access to oxygen, nutrients, and vessel-derived paracrine factors. For example, brain-tropic melanoma cells are well-known to invade along or within blood vessels at the invasive front, but the molecular mechanisms that guide this process are not well-characterized. We have used melanoma cells of different phenotypic states (melanocytic versus mesenchymal) to characterize different modes of perivascular invasion in the brain. We find that Sox9hi mesenchymal state melanoma cells undergo pericyte-like spreading along brain blood vessels via a Snail1-dependent process; in contrast, Sox10hi melanocytic state melanoma form proliferative, perivascular clusters. Snai1 deletion in mesenchymal-state melanoma cells diminishes Tgf{beta}-induced expression of Pdgfr{beta} which impairs Tgf{beta}/Pdgf ligand-driven motility along the brain microvasculature and dramatically reduces perivascular dispersal of melanoma cells throughout the brain post-colonization. These data suggest that, depending on their transcriptional/phenotypic state, some melanoma cells may appropriate signals that typically mediate endothelial cell:pericyte cross talk as an adaptive mechanism for maintaining vessel proximity and motility within the brain microenvironment.

cancer biology↗

bioRxiv2022

Periostin+ stromal cells guide lymphovascular invasion by cancer cells

Cancer cell dissemination to the sentinel lymph node associates with poor patient outcomes, particularly in breast cancers. How cancer cells egress the primary tumor upon interfacing with the lymphatic vasculature is complex and driven by dynamic interactions between cancer cells and stromal cells including cancer associated fibroblasts (CAFs). The matricellular protein periostin can distinguish CAF subtypes in breast cancer and is associated with increased desmoplasia and disease recurrence in patients. However, since periostin is secreted, periostin-expressing CAFs are difficult to characterize in situ, limiting our understanding of their specific contribution to cancer progression. Here, we used in vivo genetic labelling and ablation to lineage trace periostin+ cells and characterize their function(s) during tumor growth and metastasis. We report that periostin-expressing CAFs are spatially found at periductal and perivascular margins, are enriched at lymphatic vessel peripheries, and are differentially activated by highly-metastatic cancer cells versus low-metastatic counterparts. Surprisingly, genetically depleting periostin+ CAFs slightly accelerated primary tumor growth but impaired intratumoral collagen organization and inhibited lymphatic, but not lung, metastases. Periostin ablation in CAFs impaired their ability to deposit aligned collagen matrices and inhibited cancer cell invasion through collagen and across lymphatic endothelial cell monolayers. Thus, highly-metastatic cancer cells mobilize periostin-expressing CAFs in the primary tumor site which promote collagen remodeling and collective cell invasion within lymphatic vessels and ultimately to sentinel lymph nodes. Significance StatementMetastatic disease causes the majority of cancer-related deaths but is challenging to treat as it is a complex multi-step process driven by heterotypic cell interactions. Cancer-associated fibroblasts (CAFs) are abundant in most solid tumors and display pro-tumorigenic and pro-metastatic functions, but extensive molecular diversity among CAFs has yielded contradictory results in previous attempts to target this population. Therefore, there is a need to identify markers of CAF subpopulations that promote or inhibit metastasis and functionally characterize them to understand their contributions during tumor progression. Our work identifies a population of CAFs, marked by expression of the matricellular protein periostin, that remodel the ECM to promote the escape of cancer cells into lymphatic vessels thereby driving colonization of proximal lymph nodes.

cancer biology↗