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  3. Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching

Cancer cells sense solid stress to enhance metastasis by CKAP4 phase separation-mediated microtubule branching

  • Cell Discov. 2024 Nov 12;10(1):114. doi: 10.1038/s41421-024-00737-1.
Xing Sun 1 2,  Yangyang Zhou 2,  Shengjie Sun 1,  Siyuan Qiu 1 2,  Menglan Peng 2,  Han Gong 1,  Junxiao Guo 2,  Chengcai Wen 1,  Yibin Zhang 1 2,  Yifang Xie 1,  Hui Li 1 3,  Long Liang 1,  Guoyan Luo 4,  Wencan Wu 5 6,  Jing Liu 7,  Weihong Tan 8 9 10,  Mao Ye 11
Affiliations

Affiliations

  • 1 Department of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, China.
  • 2 Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, China.
  • 3 Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 Hangzhou Institute of Medicine (HIM), The Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 5 The Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. wuwencan118@163.com.
  • 6 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, China. wuwencan118@163.com.
  • 7 Department of Hematology, the Second Xiangya Hospital, Molecular Biology Research Center, Center for Medical Genetics, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, China. jingliucsu@hotmail.com.
  • 8 Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, China. tan@hnu.edu.cn.
  • 9 Hangzhou Institute of Medicine (HIM), The Chinese Academy of Sciences, Hangzhou, Zhejiang, China. tan@hnu.edu.cn.
  • 10 Institute of Molecular Medicine (IMM), Renji Hospital, Shanghai Jiao Tong University School of Medicine, and College of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai, China. tan@hnu.edu.cn.
  • 11 Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, China. goldleaf@hnu.edu.cn.
PMID: 39528501 DOI: 10.1038/s41421-024-00737-1
Abstract

Solid stress, originating from rigid and elastic components of extracellular matrix and cells, is a typical physical hallmark of tumors. Mounting evidence indicates that elevated solid stress drives metastasis and affects prognosis. However, the molecular mechanism of how Cancer cells sense solid stress, thereby exacerbating malignancy, remains elusive. In this study, our clinical data suggest that elevated stress in metastatic solid tumors is highly associated with the expression of cytoskeleton-associated protein 4 (CKAP4). Intriguingly, CKAP4, as a sensitive intracellular mechanosensor, responds specifically to solid stress in a subset of studied tumor micro-environmental elements through liquid-liquid phase separation. These micron-scaled CKAP4 puncta adhere tightly onto microtubules and dramatically reorchestrate their curvature and branching to enhance cell spreading, which, as a result, boosts Cancer cell motility and facilitates distant metastasis in vivo. Mechanistically, the intrinsically disordered region 1 (IDR1) of CKAP4 binds to microtubules, while IDR2 governs phase separation due to the CAv1.2-dependent calcium influx, which collectively remodels microtubules. These findings reveal an unprecedented mechanism of how Cancer cells sense solid stress for Cancer malignancy and bridge the gap between Cancer physics and cancer Cell Biology.

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