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The work evaluates two limitations of standalone approaches—reversing ECM stiffening and interrupting cancer-cell responses to mechanical cues—then integrates them into a synergistic anticancer strategy. Using immunofluorescence on 181 tissue chips and TCGA mRNA-sequencing, ECM stiffness is shown to modulate tumor phenotypes, with YAP1/ABHD11-AS1/STAU2/ZYX/p-YAP1 signaling serving as a key entry 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Targeting ECM Stiffness: Integration of Matrix Softening and Mechanical Signal Transduction Blockade in Primary Liver Cancers  \nZefeng Shen, Liye Tao, Yali Wang, Yiwei Zhu, Haoyu Pan, Yijun Li, Shi Jiang, Junhao Zheng, Jingwei Cai, Yang Liu, Kainan Lin, Shihao Li, Yifan Tong, Liqing Shangguan,* Junjie Xu,* and Xiao Liang*  \nThe development of primary liver cancer (hepatocellular carcinoma [HCC] and intrahepatic cholangiocarcinoma [ICC]) is linked to its physical microenvironment, particularly extracellular matrix (ECM) stiffness. Potential anticancer strategies targeting ECM stiffness include prevention/reversal of the stiffening process and disruption of the response of cancer cells to mechanical signals from ECM. However, each strategy has limitations. Therefore, the authors propose integrating them to maximize their strengths. Compared with HCC, ICC has a stiffer ECM and a worse prognosis. Therefore, ICC is selected to investigate mechanisms underlying the influence ofECMstiffness on cancer progression and application of the integrated anticancer strategy targeting ECM stiffness. In summary, immunofluorescence results for 181 primary liver cancer tissue chips (ICC, n = 91; HCC, n = 90) and analysis of TCGA mRNA-sequencing demonstrate that ECM stiffness can affect phenotypes of primary liver cancers. The YAP1/ABHD11-AS1/STAU2/ZYX/p– YAP1 pathway is a useful entry point for exploration of specific mechanisms of mechanical signal conduction from the ECM in ICC cells and their impact on cancer progression. Moreover, a synergistic anticancer strategy targeting ECMstiffness (ICCM@NPs + siABHD11-AS1@BAPN) is constructed by integrating ECM softening and blocking intracellular mechanical signal transduction in ICC and can provide insights for the treatment of cancers characterized by stiff ECM.  \n1. Background  \nThe extracellular matrix (ECM), which is composed of collagens, fibronectin, glycosaminoglycans, elastin, laminins, and various combinations of these molecules, creates a non-cellular macromolecular framework in 3D space. [1] In the context of solid malignancies, the disruption of proper ECM homeostasis is often considered a defining characteristic. [2,3] The ECM is important in cancer biology, providing mechanical support, modulating the microenvironment, and serving as a source of signaling molecules. [2,4] Thereis a growing body of evidence suggesting that the development of cancer is strongly influenced by the physical properties of the ECM, particularly its stiffness. [5–7] When a tumor develops, the ECM tends to becomestiffer. This tendency can be attributed to several factors, including enhanced matrix deposition, collagen cross-linking,fiber stiffening, elevated cell density, heightened interstitial fluid pressure, and intensified cell-to-cell interactions. [8] Increased ECM stiffness is not only a common feature of various types of cancer  \nZ. Shen, L. Tao, Y. Wang, H. Pan, J. Zheng, J. Cai, Y. Liu, K. Lin, S. Li,  \nY. Tong, J. Xu, X. Liang  \nZhejiang Key Laboratory of Multi-omics Precision Diagnosis and  \nTreatment of Liver Diseases Department of General Surgery Sir Run Run Shaw Hospital  \nZhejiang University School of Medicine Hangzhou, Zhejiang 310016, China  \n[E-mail:](E-mail: walter235@zju.edu.cn)[ walter235@zju.edu.cn](E-mail: walter235@zju.edu.cn); [srrshlx@zju.edu.cn](srrshlx@zju.edu.cn)  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202403040](https://doi.org/10.1002/advs.202403040)[ ](https://doi.org/10.1002/advs.202403040)© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202403040  \nZ. Shen, L. Tao, Y. Wang, H. Pan, J.","cbCaioFo2w6U7TkC","https://ap.wps.com/l/cbCaioFo2w6U7TkC","pdf",15885919,21,"English","# Background\n## ECM and stiffness in solid malignancies\n## Rationale for primary liver cancer as a model\n## Patient- and data-based evidence for ECM stiffness effects","[{\"question\":\"Why is ECM stiffness important in primary liver cancer progression?\",\"answer\":\"The ECM stiffness shapes the tumor microenvironment by influencing growth, survival, migration, and related processes such as epithelial–mesenchymal transition.\"},{\"question\":\"What limitation motivates combining matrix softening with blockade of mechanical signal transduction?\",\"answer\":\"Targeting ECM stiffness through either reversing stiffening or blocking mechanosignal responses has limitations when used alone, so integration is proposed to maximize their strengths.\"},{\"question\":\"How is the ECM stiffness effect supported by experimental and bioinformatic data in the study?\",\"answer\":\"Immunofluorescence results from primary liver cancer tissue chips and TCGA mRNA-sequencing analysis indicate that ECM stiffness can alter phenotypes of primary liver cancers.\"}]","Synergistic Anticancer Strategy Targeting ECM Stiffness - Integration of Matrix Softening and Mechanical Signal Transduction Blockade in Primary Liver Cancers | PDF",1789985971,53]