Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy.

Autor:	Burchard PR; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Ruffolo LI; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Ullman NA; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Dale BS; Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA., Dave YA; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Hilty BK; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Ye J; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Georger M; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Jewell R; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Miller C; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., De Las Casas L; Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA., Jarolimek W; Drug Discovery, Syntara Ltd., Sydney, New South Wales, Australia., Perryman L; Drug Discovery, Syntara Ltd., Sydney, New South Wales, Australia., Byrne MM; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Loria A; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Marin C; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Chávez Villa M; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Yeh JJ; Departments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA., Belt BA; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Linehan DC; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.; Department of Surgery, Division of Surgical Oncology, University of Rochester Medical Center, Rochester, New York, USA., Hernandez-Alejandro R; Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.; Division of Solid Organ Transplant Surgery, Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Jazyk:	angličtina
Zdroj:	Hepatology communications [Hepatol Commun] 2024 Aug 05; Vol. 8 (8). Date of Electronic Publication: 2024 Aug 05 (Print Publication: 2024).
DOI:	10.1097/HC9.0000000000000502
Abstrakt:	Background: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. Methods: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. Results: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. Conclusions: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA. (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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