TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

Benjamin J. Dwyer; Edward J. Jarman; Jully Gogoi-Tiwari; Sofía Ferreira-Gonzalez; Luke Boulter; Rachel V Guest; Timothy J. Kendall; Dominic Thekkedath Kurian; Alastair M. Kilpatrick; Andrew J. Robson; Eoghan O'Duibhir; Tak Yung Man; Lara Campana; Philip J. Starkey Lewis; Stephen J Wigmore; John K Olynyk; Grant A Ramm; Janina E E Tirnitz-Parker; Stuart J Forbes

doi:10.1016/j.jhep.2020.11.018

TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

Benjamin J. Dwyer, Edward J. Jarman, Jully Gogoi-Tiwari, Sofía Ferreira-Gonzalez, Luke Boulter, Rachel V Guest, Timothy J. Kendall, Dominic Thekkedath Kurian, Alastair M. Kilpatrick, Andrew J. Robson, Eoghan O'Duibhir, Tak Yung Man, Lara Campana, Philip J. Starkey Lewis, Stephen J Wigmore, John K Olynyk, Grant A Ramm, Janina E E Tirnitz-Parker, Stuart J Forbes

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and associated with poor prognosis. New therapeutic strategies are urgently required. 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. Its role in CCA remains undefined. Methods: The expression of 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 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 TWEAK/Fn14 downstream functions. 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) 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.

Original language	English
Pages (from-to)	1-72
Journal	Journal of Hepatology
Volume	n/a
Early online date	19 Nov 2020
DOIs	https://doi.org/10.1016/j.jhep.2020.11.018
Publication status	E-pub ahead of print - 19 Nov 2020

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Ben Dwyer - AAMAccepted author manuscript, 5.3 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

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Dominic Thekkedath Kurian (Manager)
Royal (Dick) School of Veterinary Studies
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Stuart Forbes
- Deanery of Clinical Sciences - Chair of Transplantation and Regenerative Medicine
- Centre for Regenerative Medicine
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Dwyer, B. J., Jarman, E. J., Gogoi-Tiwari, J., Ferreira-Gonzalez, S., Boulter, L., Guest, R. V., Kendall, T. J., Thekkedath Kurian, D., Kilpatrick, A. M., Robson, A. J., O'Duibhir, E., Man, T. Y., Campana, L., Starkey Lewis, P. J., Wigmore, S. J., Olynyk, J. K., Ramm, G. A., Tirnitz-Parker, J. E. E., & Forbes, S. J. (2020). TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. Journal of Hepatology, n/a, 1-72. Advance online publication. https://doi.org/10.1016/j.jhep.2020.11.018

@article{0a334bc2c3404d4b84277a0a08873840,

title = "TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.",

abstract = "Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and associated with poor prognosis. New therapeutic strategies are urgently required. 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. Its role in CCA remains undefined. Methods: The expression of 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 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 TWEAK/Fn14 downstream functions. 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) 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.",

author = "Dwyer, {Benjamin J.} and Jarman, {Edward J.} and Jully Gogoi-Tiwari and Sof{\'i}a Ferreira-Gonzalez and Luke Boulter and Guest, {Rachel V} and Kendall, {Timothy J.} and {Thekkedath Kurian}, Dominic and Kilpatrick, {Alastair M.} and Robson, {Andrew J.} and Eoghan O'Duibhir and Man, {Tak Yung} and Lara Campana and {Starkey Lewis}, {Philip J.} and Wigmore, {Stephen J} and Olynyk, {John K} and Ramm, {Grant A} and Tirnitz-Parker, {Janina E E} and Forbes, {Stuart J}",

year = "2020",

month = nov,

day = "19",

doi = "10.1016/j.jhep.2020.11.018",

language = "English",

volume = "n/a",

pages = "1--72",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

}

Dwyer, BJ, Jarman, EJ, Gogoi-Tiwari, J, Ferreira-Gonzalez, S , Boulter, L , Guest, RV , Kendall, TJ , Thekkedath Kurian, D , Kilpatrick, AM, Robson, AJ, O'Duibhir, E, Man, TY, Campana, L, Starkey Lewis, PJ, Wigmore, SJ, Olynyk, JK, Ramm, GA, Tirnitz-Parker, JEE & Forbes, SJ 2020, 'TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.', Journal of Hepatology, vol. n/a, pp. 1-72. https://doi.org/10.1016/j.jhep.2020.11.018

TY - JOUR

T1 - TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

AU - Dwyer, Benjamin J.

AU - Jarman, Edward J.

AU - Gogoi-Tiwari, Jully

AU - Ferreira-Gonzalez, Sofía

AU - Boulter, Luke

AU - Guest, Rachel V

AU - Kendall, Timothy J.

AU - Thekkedath Kurian, Dominic

AU - Kilpatrick, Alastair M.

AU - Robson, Andrew J.

AU - O'Duibhir, Eoghan

AU - Man, Tak Yung

AU - Campana, Lara

AU - Starkey Lewis, Philip J.

AU - Wigmore, Stephen J

AU - Olynyk, John K

AU - Ramm, Grant A

AU - Tirnitz-Parker, Janina E E

AU - Forbes, Stuart J

PY - 2020/11/19

Y1 - 2020/11/19

N2 - Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and associated with poor prognosis. New therapeutic strategies are urgently required. 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. Its role in CCA remains undefined. Methods: The expression of 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 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 TWEAK/Fn14 downstream functions. 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) 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.

AB - Background & Aims: Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and associated with poor prognosis. New therapeutic strategies are urgently required. 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. Its role in CCA remains undefined. Methods: The expression of 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 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 TWEAK/Fn14 downstream functions. 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) 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.

U2 - 10.1016/j.jhep.2020.11.018

DO - 10.1016/j.jhep.2020.11.018

M3 - Article

SN - 0168-8278

VL - n/a

SP - 1

EP - 72

JO - Journal of Hepatology

JF - Journal of Hepatology

ER -

TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression.

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