CTGF/VEGFA-activated Fibroblasts Promote Tumor Migration Through Micro-environmental Modulation

Area of Science:

• Oncology
• Cell Biology
• Cancer Metastasis

Background:

• Fibroblast activation contributes to tumor progression and metastasis.
• The initial signals triggering fibroblast activation by tumors are largely unknown.
• Tumor-derived signals are hypothesized to be secreted and diffusible due to limited physical contact in early-stage lesions.

Purpose of the Study:

• To identify the initial tumor-secreted signals that activate fibroblasts.
• To elucidate the signaling pathways involved in tumor-induced fibroblast activation.
• To characterize the functional changes in fibroblasts activated by tumor signals.

Main Methods:

• Pulsed metabolic labeling and click-chemistry based affinity enrichment to screen the ductal carcinoma secretome.
• Immuno-depletion/supplementation assays to identify specific activating factors.
• Analysis of fibroblast morphology, growth, secretion profiles, and signaling pathways (ROCK1, JunB).

Main Results:

• Tumor-secreted CTGF (connective tissue growth factor) and VEGFA (vascular endothelial growth factor A) were identified as sufficient to activate mammary fibroblasts.
• Activated fibroblasts exhibited altered morphology, growth patterns, and a tumor-like secretion profile.
• Activation occurred via ROCK1 (Rho-associated coiled-coil kinase 1) and JunB signaling pathways.
• Activated fibroblasts promoted tumor migration by counteracting oxidative and lactate stress.

Conclusions:

• CTGF and VEGFA are key tumor-derived signals that initiate fibroblast activation.
• Tumor-activated fibroblasts adopt a pro-metastatic phenotype, supporting tumor progression.
• Targeting the initial fibroblast activation process presents a potential strategy for preventing metastasis.