TNF-receptor-1 adaptor protein FAN mediates TNF-induced B16 melanoma motility and invasion

Abstract

Background:Locomotion of cancer cells can be induced by TNF and other motogenic factors secreted by cells of the tumour microenvironment such as macrophages. Based on our recent findings that the TNF receptor adaptor protein FAN mediates TNF-induced actin reorganisation and regulates the directed migration of immune cells responding to chemotactic cues, we addressed the role of FAN in cancer cell motility and the formation of invadopodia, a crucial feature in tumour invasion.Methods:In B16 mouse melanoma cells, FAN was downregulated and the impact on FAN on cell motility and invasion was determined using in vitro assays and in vivo animal models.Results:Like FAN−/− murine embryonic fibroblasts, FAN-deficient B16 melanoma cells showed defective motility responses to TNF in vitro. In vivo FAN-deficient B16 melanoma cells produced significantly less disseminated tumours after i.v. injection into mice. Danio rerio used as a second in vivo model also revealed impaired spreading of FAN-deficient B16 melanoma cells. Furthermore, FAN mediated TNF-induced paxillin phosphorylation, metalloproteinase activation and increased extracellular matrix degradation, the hallmarks of functionally active invadopodia.Conclusion:The results of our study suggest that FAN through promoting melanoma cellular motility and tumour invasiveness is critical for the tumour-promoting action of TNF.

Autophagy-mediated tumor cell survival and progression of breast cancer metastasis to the brain

“…Other studies have identified genes from BC clinical samples, such as cyclooxygenase COX2 (also known as PTGS2), the epidermal growth factor receptor (EGFR) ligand HBEGF, and the brain-specific 2,6-sialyltransferase ST6GALNAC5 as mediators of BC cell passage through the BBB [83]. Cancer cells need to secrete matrix metalloproteinases (MMPs) and other proteases to disrupt the basement membrane and tight junctions as occurs in metastasis to other distant sites [96][97][98]. It has been demonstrated that secretion of MMP2, MMP3, and MMP9 by metastatic BC cells is playing a crucial role in BCBM [99].…”

Brain metastasis: Unique challenges and open opportunities

“…Because tight junctions are composed of a variety of proteins, cancer cells need to express several proteases in order to penetrate intact tight junctions [58]. Alternatively, these junctions can be destabilized by a variety of cytokines, chemokines, and inflammatory mediators frequently expressed by cancer cells, including VEGF, basic fibroblast growth factor (bFGF), transforming growth factor–β (TGF-β), interleukin-1β (IL-1β), TNF-α, interferon-γ (IFN-γ ), CCL2, CXCL8, and prostaglandin-endoperoxide synthase 2 (COX2) [56, 59–61]; cancer cells can secrete MMPs and other proteases to disrupt the basement membrane (BM), as occurs in metastasis to other sites [59, 62]. Recently, cancer cells have been shown to actively induce endothelial cell death by heterotypic signaling [63].…”

MS/MS‐based strategies for proteomic profiling of invasive cell structures

“…B). These include a range of upstream signalling molecules, such as RTKs (EGFR, ERBB2, ERBB4, EphB2, VEGFR2) and RTK ligands (EGF, HB‐EGF, EPGN/Epigen, HGF, VEGF‐A) , other secreted ligands (in particular TNF and WNT5A) , other cell surface molecules, non‐RTKs, adaptor proteins (Tks5, Crk, Grb2) , components of PI3K, Ras and MAPK signalling cascades and proteins implicated in regulation of vesicle‐mediated transport and cytoskeleton remodelling. Additionally, a large separate group gathers proteins associated with ECM remodelling and proteolytic ECM degradation.…”