Pathogenic role and regulatory mechanism of tumor-associated macrophage to cancer-associated fibroblast transition during cancer progression

Ph.D. ; Cancer-associated fibroblasts (CAF) are highly heterogeneous and their origins are largely unknown. Recently, we revealed that bone marrow-derived macrophages (BMDM) can transdifferentiate into myofibroblasts locally at the inflammatory site in a Smad3-dependent manner, but its potential role in the tumor microenvironment (TME) is still unexplored. Thus, we hypothesize that tumor-associated macrophages (TAM) may be able to transit into CAF, termed TAM to CAF transition (TAM-CAF), in TME during cancer progression. ; We first examined the TAM-CAF transition in cancer patients by confocal microscopy, flow cytometry analysis and tissue microarray study and discovered the existence of α-SMA⁺ CD68⁺ TAM-CAF cells in the TME of lung, liver, prostate and kidney cancer patients, where TAM-CAF was significantly associated with the mortality of non-small cell lung carcinoma (NSCLC). The TAM-CAF transition was further determined by using a fate mapping study on LysM-tdTomato mice bearing syngeneic lung carcinoma LLC. We detected a rich population of macrophage-linage derived CAF (α-SMA⁺ tdTomato⁺) which peaked at the early tumorigenesis stage and accounted for ~45% of the total CAF in the LLC-tumor; suggesting TAM-CAF is an important CAF source during cancer development. ; Furthermore, we characterized that TAM-CAF cells derived from cancer secretome stimulated BMDM expressed markers and effectors of CAF in vitro, and found that the transcriptomic profile of TAM-CAF cells in NSCLC biopsy was CAF-dominated and associated with TGF-β1 signaling and angiogenesis. The pathogenic role of TAM-CAF cells in cencer progression was examined by adoptive transferring BMDM-derived myofibroblasts onto tumor-bearing immunodeficient (NOD/SCID) and macrophage-depleted (LysM-iDTR) mice. Surprisingly, transfer with TAM-CAF cells significantly promoted the cancer progression associated with the markedly increment of angiogenesis in vivo. ; Mechanistically, we detected a Smad3-dependent mechanism in TAM-CAF transition as CD68⁺α-SMA⁺ cells ...