Paul R Burchard, Luis I Ruffolo, Nicholas A Ullman, Benjamin S Dale, Yatee A Dave, Bailey K Hilty, Jian Ye, Mary Georger, Rachel Jewell, Christine Miller, Luis De Las Casas, Wolfgang Jarolimek, Lara Perryman, Matthew M Byrne, Anthony Loria, Chelsea Marin, Mariana Chávez Villa, Jen Jen Yeh, Brian A Belt, David C Linehan, Roberto Hernandez-Alejandro
{"title":"泛赖氨酸氧化酶抑制剂可破坏纤维炎性肿瘤基质，使胆管癌易于接受化疗。","authors":"Paul R Burchard, Luis I Ruffolo, Nicholas A Ullman, Benjamin S Dale, Yatee A Dave, Bailey K Hilty, Jian Ye, Mary Georger, Rachel Jewell, Christine Miller, Luis De Las Casas, Wolfgang Jarolimek, Lara Perryman, Matthew M Byrne, Anthony Loria, Chelsea Marin, Mariana Chávez Villa, Jen Jen Yeh, Brian A Belt, David C Linehan, Roberto Hernandez-Alejandro","doi":"10.1097/HC9.0000000000000502","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299993/pdf/","citationCount":"0","resultStr":"{\"title\":\"Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy.\",\"authors\":\"Paul R Burchard, Luis I Ruffolo, Nicholas A Ullman, Benjamin S Dale, Yatee A Dave, Bailey K Hilty, Jian Ye, Mary Georger, Rachel Jewell, Christine Miller, Luis De Las Casas, Wolfgang Jarolimek, Lara Perryman, Matthew M Byrne, Anthony Loria, Chelsea Marin, Mariana Chávez Villa, Jen Jen Yeh, Brian A Belt, David C Linehan, Roberto Hernandez-Alejandro\",\"doi\":\"10.1097/HC9.0000000000000502\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. 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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.</p><p><strong>Conclusions: </strong>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. 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引用次数: 0
摘要
背景：胆管癌（CCA）具有高度脱膜的基质，可促进结构和功能上的耐药性。赖氨酰氧化酶（LOX，LOXL1-4）可催化胶原交联，从而增加基质的刚性并促进耐药性的产生。在此，我们评估了赖氨酰氧化酶在基质脱钙化中的作用以及抑制泛赖氨酰氧化酶（pan-LOX）对 CCA 的影响：方法：从档案组织中分析切除的CCA和正常肝脏标本。方法：从档案组织中分析切除的 CCA 和正常肝脏标本，并使用肝内 CCA（iCCA）自发模型和正位小鼠模型评估泛酰氧化酶抑制剂 PXS-5505 在治疗和相关研究中的影响。通过体内和体外实验对泛LOX抑制剂的功能作用进行了研究：结果：所有 5 种赖氨酸氧化酶在 CCA 中均上调，赖氨酸氧化酶表达的减少与切除的 CCA 患者预后的改善相关。肝内胆管癌的自发和正位小鼠模型会上调所有 5 种赖氨酸氧化酶同工酶。Pan-LOX 抑制可逆转对肿瘤血管的机械压迫，从而改善化疗的穿透性和细胞毒性疗效。化疗与 Pan-LOX 抑制相结合可增加损伤相关分子模式的释放，这与抗肿瘤 T 细胞反应的改善有关。Pan-LOX抑制可降低体外巨噬细胞的侵袭特征，使肿瘤相关巨噬细胞更容易接受化疗。携带正位和自发性肝内胆管癌肿瘤的小鼠在pan-LOX抑制与化疗相结合后，肿瘤生长延迟，生存率提高：结论：CCA 会上调全部 5 种赖氨酸氧化酶同工酶，而泛 LOX 抑制剂可逆转与化疗耐药性相关的肿瘤诱导机械力，从而提高化疗疗效并重塑抗肿瘤免疫反应。因此，pan-LOX抑制剂联合疗法是CCA的一种创新治疗策略。
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.
期刊介绍：
Hepatology Communications is a peer-reviewed, online-only, open access journal for fast dissemination of high quality basic, translational, and clinical research in hepatology. Hepatology Communications maintains high standard and rigorous peer review. Because of its open access nature, authors retain the copyright to their works, all articles are immediately available and free to read and share, and it is fully compliant with funder and institutional mandates. The journal is committed to fast publication and author satisfaction.
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