T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy.
T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy.
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T细胞通过调控化疗后细胞外基质重塑来促进转移。
DOI：
10.1158/0008-5472.can-21-1012
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发表时间：
2022-01-15
期刊：
影响因子：
11.2
通讯作者：
Shaked Y
中科院分区：
文献类型：
--
作者：
Haj-Shomaly J;Vorontsova A;Barenholz-Cohen T;Levi-Galibov O;Devarasetty M;Timaner M;Raviv Z;Cooper TJ;Soker S;Hasson P;Weihs D;Scherz-Shouval R;Shaked Y
化疗通过上调 T 细胞中的 LOX 来诱导转移性肺 ECM 重塑，LOX 抑制剂可以靶向 T 细胞来抑制转移。转移是癌症相关死亡的主要原因。尽管人们努力了解转移过程的机制，但转移性癌症的治疗仍然具有挑战性。在这里，我们描述了化疗诱导的宿主介导的机制，该机制促进细胞外基质（ECM）的重塑，最终促进癌细胞的播种和转移。紫杉醇 (PTX) 化疗增强了无肿瘤小鼠肺部的快速 ECM 重塑和机械结构变化，并且 ECM 重塑酶赖氨酰氧化酶 (LOX) 的蛋白表达和活性随着 PTX 的增加而增加。具有 LOX 基因缺失的嵌合小鼠模型表明，化疗诱导的 ECM 重塑是由表达 LOX 的 CD8+ T 细胞介导的。一致地，将 CD8+ T 细胞（而非 CD4+ T 细胞或 B 细胞）从 PTX 治疗的小鼠过继转移至免疫剥夺小鼠体内，可诱导肺 ECM 重塑。最后，在临床相关的转移性乳腺癌模型中，LOX 抑制抵消了 PTX 促进转移、ECM 相关的作用。这项研究强调了免疫细胞在化疗后调节 ECM 和转移中的作用，表明抑制化疗诱导的 ECM 重塑是转移性癌症的潜在治疗策略。化疗通过上调 T 细胞中的 LOX 来诱导转移性肺 ECM 重塑，LOX 抑制剂可以靶向 T 细胞来抑制转移。 参见 Kolonin 和 Woodward 的相关评论，第 17 页。 197
Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis. 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. 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