Abstract Body (Do not enter title and authors here): Rationale: Smooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases like atherosclerosis and pulmonary hypertension, but their role in tumorigenesis is unknown.
Objective: To investigate SMC diversity and plasticity in tumor angiogenesis and its underlying molecular drivers.
Methods and Results: Here we use SMC-specific lineage-tracing mouse models and single cell RNA sequencing (scRNA-seq) to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that around 10% of SMCs adopt a phenotype which includes features traditionally associated with macrophage-like cells, suggesting they may contribute to the immune profile of the tumor microenvironment (TME). These cells are transcriptionally similar to ‘resolution phase’ M2b macrophages, which have been described to have a role in inflammation resolution. Signaling from bone marrow stromal antigen 2 (BST2) on the surface of tumor cells to PIRA2 on SMC promotes this phenotypic transition, leading to a SMC phenotype that is more proliferative, migratory, and phagocytic. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and the cells that were able to transition had a comparatively higher inflammatory signal typically associated with anti-tumor effect.
Conclusions: As BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. The novel concept of SMC contribution to the immune landscape suggests manipulation of SMC phenotypic switching as an approach to altering cancer pathogenesis. Further translational work is needed to understand how this phenotypic switch could influence response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.