CCBIO seminar: Cédric Gaggioli
Production of LIF cytokine by cancer cells and fibroblasts contributes to the establishment of a pro-invasive tumor microenvironment
Institute for Research on Cancer and Aging (IRCAN), Nice, France
Tumor-stroma signaling crosstalk contributes to tumor microenvironment modifications and cancer cell spreading. Carcinoma associated fibroblasts (CAF) display enhanced extracellular matrix remodeling capacities and formation of a pro-invasive tumor microenvironment, which enables carcinoma cell collective invasion. The transforming growth factor-β (TGF-β) cytokine-dependent signaling pathway was considered the major CAF activator. Using three dimensional organotypic invasion assays, we investigated the molecular mechanisms of the TGF-β1-dependent signaling that mediates the pro-invasive fibroblast activation.
We demonstrate that TGF-β-induced production of the leukemia inhibitory factor (LIF) cytokine by both cancer cells and fibroblasts is responsible for the pro-invasive tumor microenvironment modifications. LIF cytokine stimulation of human dermal fibroblasts activates pro-invasive track formation in a GP130/JAK1/STAT3-specific signaling pathway. We show that LIF mediates TGF-β-dependent acto-myosin contractility leading to collagen fiber assembly. Human carcinoma cell lines from different organs (skin, head and neck, breast and colon) and human melanoma cell lines induce pro-invasive fibroblast activation in vitro through direct secretion of LIF. Moreover, detection of LIF cytokine in human carcinoma specimens indicated that LIF is significantly up-regulated in tumor tissues and correlated with poor clinical outcome. Finally, an orthotopic mice model of breast carcinoma demonstrates that LIF production correlates with tumor microenvironment collagen fiber organization and cancer cell invasion in vivo.
These results disclose the molecular mechanisms underlying the pro-invasive activation of stromal fibroblasts in tumor contexts and identify LIF cytokine as a key player in the process. They also suggest that blocking JAK1 kinase expression in CAF may present potential therapeutic benefits for patients with aggressive carcinoma.
Chairperson: Donald Gullberg, CCBIO