T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy.

Haj-Shomaly, Jozafina; Vorontsova, Avital; Barenholz-Cohen, Tamar; Levi-Galibov, Oshrat; Devarasetty, Mahesh; Timaner, Michael; Raviv, Ziv; Cooper, Tim J; Soker, Shay; Hasson, Peleg; Weihs, Daphne; Scherz-Shouval, Ruth; Shaked, Yuval

Haj-Shomaly, Jozafina; Vorontsova, Avital; Barenholz-Cohen, Tamar; Levi-Galibov, Oshrat; Devarasetty, Mahesh; Timaner, Michael; Raviv, Ziv; Cooper, Tim J; Soker, Shay; Hasson, Peleg; Weihs, Daphne; Scherz-Shouval, Ruth; Shaked, Yuval.

Afiliación

Haj-Shomaly J; Rappaport Technion Integrated Cancer Center, Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Vorontsova A; Rappaport Technion Integrated Cancer Center, Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Barenholz-Cohen T; Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
Levi-Galibov O; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
Devarasetty M; Wake Forest University School of Medicine, Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina.
Timaner M; Rappaport Technion Integrated Cancer Center, Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Raviv Z; Rappaport Technion Integrated Cancer Center, Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Cooper TJ; Rappaport Technion Integrated Cancer Center, Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Soker S; Wake Forest University School of Medicine, Wake Forest Institute for Regenerative Medicine, Winston-Salem, North Carolina.
Hasson P; Department of Genetics and Developmental Biology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Weihs D; Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
Scherz-Shouval R; Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
Shaked Y; Rappaport Technion Integrated Cancer Center, Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. yshaked@technion.ac.il.

Cancer Res ; 82(2): 278-291, 2022 01 15.

Article en En | MEDLINE | ID: mdl-34666995

RESUMEN

Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8+ T cells expressing LOX. Consistently, adoptive transfer of CD8+ T cells, but not CD4+ T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer. SIGNIFICANCE: Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis.See related commentary by Kolonin and Woodward, p. 197.

Asunto(s)

Antineoplásicos Fitogénicos/efectos adversos; Neoplasias de la Mama/metabolismo; Linfocitos T CD8-positivos/metabolismo; Matriz Extracelular/efectos de los fármacos; Matriz Extracelular/metabolismo; Neoplasias Pulmonares/inducido químicamente; Neoplasias Pulmonares/secundario; Neoplasias Mamarias Experimentales/metabolismo; Neoplasias Mamarias Experimentales/patología; Paclitaxel/efectos adversos; Traslado Adoptivo/métodos; Animales; Antineoplásicos Fitogénicos/administración & dosificación; Neoplasias de la Mama/patología; Linfocitos T CD8-positivos/inmunología; Proteínas de la Matriz Extracelular/genética; Proteínas de la Matriz Extracelular/metabolismo; Femenino; Humanos; Neoplasias Pulmonares/inmunología; Células MCF-7; Neoplasias Mamarias Experimentales/inmunología; Ratones; Ratones Endogámicos BALB C; Ratones Noqueados; Ratones SCID; Paclitaxel/administración & dosificación; Proteína-Lisina 6-Oxidasa/genética; Proteína-Lisina 6-Oxidasa/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Paclitaxel / Linfocitos T CD8-positivos / Matriz Extracelular / Neoplasias Pulmonares / Neoplasias Mamarias Experimentales / Antineoplásicos Fitogénicos Límite: Animals / Female / Humans Idioma: En Revista: Cancer Res Año: 2022 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Estados Unidos

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