CTGF/VEGFA-activated fibroblasts promote tumor migration through micro-environmental modulation

Fibroblast activation is associated with tumour progression and implicated in metastasis, but the initial triggering signals required to kick-start this process remain largely unknown. Since small cancerous lesions share limited physical contact with neighboring fibroblasts, we reasoned the first tumour-derived signal for fibroblast activation should be secreted and diffusible. By pulsed metabolic labeling and click-chemistry based affinity enrichment, we sieved through the ductal carcinoma secretome for potential fibroblast activators. Using immuno-depletion/supplementation assays on various secreted factors, we pinpointed that tumour-secreted CTGF/VEGFA alone is sufficient to activate paired mammary fibroblasts from the same patient via ROCK1 and JunB signaling. Fibroblasts activated in this manner are distinct in morphology, growth, and adopt a highly tumour-like secretion profile, which in turn promotes tumour migration by counteracting oxidative and lactate stress. These findings reveal a profound division-of-labor between normal and cancer cells under the directive of the latter, and allude to potential metastatic prevention through inhibiting local fibroblast activation.