TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression
Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and in...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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ELSEVIER
2021
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| Online Access: | http://purl.org/au-research/grants/nhmrc/1031330 http://hdl.handle.net/20.500.11937/84925 |
| _version_ | 1848764699735228416 |
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| author | Dwyer, Ben Jarman, E.J. Gogoi-Tiwari, Jully Ferreira-Gonzalez, S. Boulter, L. Guest, R.V. Kendall, T.J. Kurian, D. Kilpatrick, A.M. Robson, A.J. O'Duibhir, E. Man, T.Y. Campana, L. Starkey Lewis, P.J. Wigmore, S.J. Olynyk, John Ramm, G.A. Tirnitz-Parker, Nina Forbes, S.J. |
| author_facet | Dwyer, Ben Jarman, E.J. Gogoi-Tiwari, Jully Ferreira-Gonzalez, S. Boulter, L. Guest, R.V. Kendall, T.J. Kurian, D. Kilpatrick, A.M. Robson, A.J. O'Duibhir, E. Man, T.Y. Campana, L. Starkey Lewis, P.J. Wigmore, S.J. Olynyk, John Ramm, G.A. Tirnitz-Parker, Nina Forbes, S.J. |
| author_sort | Dwyer, Ben |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA.
Methods: The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis.
Results: Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206+ macrophages. Pharmacological blocking of the TWEAK downstream target chemokine monocyte chemoattractant protein 1 (MCP-1 or CCL2) significantly reduced CCA xenograft growth, while TWEAK overexpression drove cancer-associated fibroblast proliferation and collagen deposition in the tumour niche. Genetic Fn14 ablation significantly reduced inflammatory, fibrogenic and ductular responses during carcinogenic TAA-mediated injury.
Conclusion: These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth.
Lay summary: Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation. |
| first_indexed | 2025-11-14T11:23:31Z |
| format | Journal Article |
| id | curtin-20.500.11937-84925 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T11:23:31Z |
| publishDate | 2021 |
| publisher | ELSEVIER |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-849252021-08-16T02:53:48Z TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression Dwyer, Ben Jarman, E.J. Gogoi-Tiwari, Jully Ferreira-Gonzalez, S. Boulter, L. Guest, R.V. Kendall, T.J. Kurian, D. Kilpatrick, A.M. Robson, A.J. O'Duibhir, E. Man, T.Y. Campana, L. Starkey Lewis, P.J. Wigmore, S.J. Olynyk, John Ramm, G.A. Tirnitz-Parker, Nina Forbes, S.J. Science & Technology Life Sciences & Biomedicine Gastroenterology & Hepatology Cholangiocarcinoma Liver cancer TWEAK Fn14 Tumour-associated macrophage Cancer-associated fibroblast Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. Methods: The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. Results: Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206+ macrophages. Pharmacological blocking of the TWEAK downstream target chemokine monocyte chemoattractant protein 1 (MCP-1 or CCL2) significantly reduced CCA xenograft growth, while TWEAK overexpression drove cancer-associated fibroblast proliferation and collagen deposition in the tumour niche. Genetic Fn14 ablation significantly reduced inflammatory, fibrogenic and ductular responses during carcinogenic TAA-mediated injury. Conclusion: These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. Lay summary: Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation. 2021 Journal Article http://hdl.handle.net/20.500.11937/84925 10.1016/j.jhep.2020.11.018 English http://purl.org/au-research/grants/nhmrc/1031330 http://purl.org/au-research/grants/nhmrc/1087125 http://purl.org/au-research/grants/nhmrc/1061332 http://creativecommons.org/licenses/by-nc-nd/4.0/ ELSEVIER fulltext |
| spellingShingle | Science & Technology Life Sciences & Biomedicine Gastroenterology & Hepatology Cholangiocarcinoma Liver cancer TWEAK Fn14 Tumour-associated macrophage Cancer-associated fibroblast Dwyer, Ben Jarman, E.J. Gogoi-Tiwari, Jully Ferreira-Gonzalez, S. Boulter, L. Guest, R.V. Kendall, T.J. Kurian, D. Kilpatrick, A.M. Robson, A.J. O'Duibhir, E. Man, T.Y. Campana, L. Starkey Lewis, P.J. Wigmore, S.J. Olynyk, John Ramm, G.A. Tirnitz-Parker, Nina Forbes, S.J. TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression |
| title | TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression |
| title_full | TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression |
| title_fullStr | TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression |
| title_full_unstemmed | TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression |
| title_short | TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression |
| title_sort | tweak/fn14 signalling promotes cholangiocarcinoma niche formation and progression |
| topic | Science & Technology Life Sciences & Biomedicine Gastroenterology & Hepatology Cholangiocarcinoma Liver cancer TWEAK Fn14 Tumour-associated macrophage Cancer-associated fibroblast |
| url | http://purl.org/au-research/grants/nhmrc/1031330 http://purl.org/au-research/grants/nhmrc/1031330 http://purl.org/au-research/grants/nhmrc/1031330 http://hdl.handle.net/20.500.11937/84925 |