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Fas Ligand: switching signals from tumor immune erosion to metastasis

Fas Ligand: switching signals from tumor immune erosion to metastasis. Bei-Chang Yang , Ph.D. ( 楊倍昌 ) Professor, Department of Microbiology and Immunology , College of Medicine , National Cheng Kung University (NCKU), Tainan, Taiwan.

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Fas Ligand: switching signals from tumor immune erosion to metastasis

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  1. Fas Ligand: switching signals from tumor immune erosion to metastasis • Bei-Chang Yang, Ph.D. (楊倍昌) • Professor, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University (NCKU), Tainan, Taiwan. • Director, Research Center for Society, Technology and Medicine (STM center); NCKU Tainan, Taiwan.

  2. Fas+ • On Tumor microenvironment and infiltrating T cells • Novel FasL signaling mechanism! • (FasL) Lin HC, et al (2013) J Biol Chem. 287:20664–20673. • Why are T cells trapped in peripheral area of tumor? • (Tenascin C) Huang JY, et al (2010) J Immunol. 185:1450-1459. • (collagen) Lin YP, et al. (2009) Mol Immunol. Mol Immunol. 46:3328-3335. • Are those infiltrating T cells alive ? • (PI3K) Su CC, et al (2007) J Immunol. 179:4589-4597. • (FasL) Hor WS, et al. (2003) J Leukocyte Biol. 73: 363-368. • Do infiltrating T cells affect tumor growth or metastasis? • (depletion study)Chen YL, et al (2002) Br J Cancer 87:359-365. • (Fas signaling) Chen YL, et al. (2003) J Immunol. 171:1183-1192. • Can they modulate consequent local immune reaction? • (IL-10 & TGF-b) Yang BC, et al. (2003) J Immunol. 171:3947-3954. • (Fas and Th17) Su CC, et al (2013) Cell Immunol. 281:101–110 FasL+

  3. Fas (1991): Nagata, S.; Krammer, P. FasL (1993): Nagata, S. & Goldstein, P. CD95/CD95-L Fas/Fas-ligand : the major signaling system for cell death. apoptosis P Krammer 長田 重一 Fas: Itoh N, et al. (1991) Cell 66: 233–243 (Nagata S) Oehm A , et al. (1992) J. Biol. Chem. 267: 10709–10715 (Krammer P) FasL: Suda T, et al. (1993) Cell 75: 1169-1178 (Nagata S; Goldstein P)

  4. Apaf-1 Caspase 9 Caspase 3 Death substrates Nature 407, 789 – 795(2000)

  5. FasL reverse signaling(FasL by itself acts as a receptor) • Suzuki I. and Fink PJ, Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand. J. Exp. Med., 187:123, 1998. • Sun M, Ames KT, Suzuki I,. Fink PJ, The Cytoplasmic Domain of Fas Ligand Costimulates TCR Signals, J. Immunol., 177, 1481, 2006. Pamela J. Fink, h.D. Department of Immunology University of Washington The cytoplasmic domain of FasL is sufficient to mediate costimulation (FasL cross-linking is required). BC Yang

  6. Conventional view of receptor-ligand interaction FasL FasL Fas

  7. Take home massage: Fas ligand hijack the Met receptor on lipid raft. Protein-protein interaction in lipid raft is an alternative way for cell signaling.

  8. The structure of FasL

  9. Due to unstable protein region (A). Full-length and truncated FasL. Adapted from Orlinick JR, et al. J Biol Chem 1997, 272:32221-29. Jodo S, et al. J Immunol 2005, 174:4470-4474. FasL-△70: deleting the N-terminal 2-70 aa; FasL-△33: deleting the N-terminal 2-33 aa.

  10. FasL enhances cell migration and invasion. A B (A) In the single cell motility assay, cell migration distance in 6 h was recorded every 5 min by time lapse video under a microscope. Total distance of cell migration was taken to represent cell mobility. (B) In invasion assay, cells were seeded on matrigel (1 mg/ml) coated transwell plates in 16 h. Invading cells were calculated for quantification. Values was shown the mean ± SEM. (* p<0.05, ** p<0.001 compared with N1, # p<0.05 compared with FasL)

  11. Truncated FasL promote cell transformation (enhances lung metastasis, anchorage-indecent growth) Lung metastasis in eight-week-old BALB/cAnN.Cg-Foxn1nu/CrlNarl nude mice anchorage-independent growth.

  12. Q: Why FasL without intracellular domain still promotes tumor metastasis? The Met tyrosine kinase receptor is a high-affinity receptor for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF-Met system is necessary for embryonic development, and aberrant MET signaling favors tumorigenesis and metastasis. cyclinD1 Metastasis

  13. Association of FasL and Met in lipid raft • Location of Met is not changed • Lipid raft formation is required MbCD:methyl-beta-cyclodextrin, a specific cholesterol-binding agent extracting cholesterol from plasma membranes

  14. Confocal imaging reveals colocalization of FasL and Met labeled cholera toxin B MF/M: Met/FasL complex/total Met FL/L:FasL in lipid raft/lipid raft ML/L:Met in lipid raft/lipid raft

  15. A FasL domain between 70-130 is important for complex with Met. NIH3T3/ aFasL (C-terminal, BD) + + + - + + + + FasL105-130 MRC5 cells/aFasL (N-20, Senta Cruz) Note: full length FasL triggered profound apoptosis in MRC5

  16. The Met tyrosine kinase receptor is a high-affinity receptor for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF-Met system is necessary for embryonic development, and aberrant MET signaling favors tumorigenesis and metastasis. cyclinD1 Metastasis

  17. Met signal is initiated and mediates transformed phenotype. • Stat3 is essential for the enhanced cell migration. Met inhibitor: PHA665752 Stst3 inhibitor: AG490

  18. B A FasL/Met complex in human tumor cells • The complex of FasL and Met is detected in various tumor cell lines. • Suppression of FasL by specific ribozyme reduces the phosphorylation of Met.

  19. lipid raft Fas/FasL signaling revised: There are three different pathways initiated by FasL. FasL-associated metastasis Autoimmunity? Fas counter-attack mechanism/ Tissue destruction?

  20. Mother nature works in a way that is not always as been told.

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