DataVXAdvanced SciencePaper
journal article·2024-12Open access

Gastric Cancer Actively Remodels Mechanical Microenvironment to Promote Chemotherapy Resistance via MSCs‐Mediated Mitochondrial Transfer

Xin He, Li Zhong, Nan Wang, Baiwei Zhao, Yannan Wang, Xinxiang Wu, Changyu Zheng, Yueheng Ruan, Jianfeng Hou, Yusheng Luo, Yuehan Yin, Yulong He, Andy Peng Xiang, Jiancheng Wang

Advanced Science· Volume 11· Issue 47
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Abstract

Abstract Chemotherapy resistance is the main reason of treatment failure in gastric cancer (GC). However, the mechanism of oxaliplatin (OXA) resistance remains unclear. Here, we demonstrate that extracellular mechanical signaling plays crucial roles in OXA resistance within GC. We selected OXA‐resistant GC patients and analyzed tumor tissues by single‐cell sequencing, and found that the mitochondrial content of GC cells increased in a biosynthesis‐independent manner. Moreover, we found that the increased mitochondria of GC cells were mainly derived from mesenchymal stromal cells (MSCs), which could repair the mitochondrial function and reduce the levels of mitophagy in GC cells, thus leading to OXA resistance. Furthermore, we investigated the underlying mechanism and found that mitochondrial transfer was mediated by mechanical signals of the extracellular matrix (ECM). After OXA administration, GC cells actively secreted ECM in the tumor microenvironment (TEM), increasing matrix stiffness of the tumor tissues, which promoted mitochondria to transfer from MSCs to GC cells via microvesicles (MVs). Meanwhile, inhibiting the mechanical‐related RhoA/ROCK1 pathway could alleviate OXA resistance in GC cells. In summary, these results indicate that matrix stiffness could be used as an indicator to identify chemotherapy resistance, and targeting mechanical‐related pathway could effectively alleviate OXA resistance and improve therapeutic efficacy.
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Research context

OpenAlex topics: Cellular Mechanics and Interactions · Caveolin-1 and cellular processes · Cancer Cells and Metastasis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Scientific Research Center The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen 518107 China

Department of Hematology The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen 518107 China

Digestive Diseases Center Guangdong Provincial Key Laboratory of Digestive Cancer Research The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen 518107 China

School of Medicine Shenzhen Campus of Sun Yat‐sen University Sun Yat‐sen University Shenzhen 518107 China

Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research The Seventh Affiliated Hospital of Sun Yat‐sen University Shenzhen 518107 China

State Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou 510060 China

Department of Joint and Trauma Surgery The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou 510630 China

Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education Sun Yat‐sen University Guangzhou 510080 China

National‐Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine Zhongshan School of Medicine Sun Yat‐sen University Guangzhou 510080 China

Department of Histoembryology and Cell Biology Zhongshan School of Medicine Sun Yat‐sen University Guangzhou 510080 China

Funding

National Key Research and Development Program of China Stem Cell and Translational Research · National Natural Science Foundation of China

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