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Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

Genes & Diseases 2024年第3期11卷 338-350页

作者： Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng State Key Laboratory of Molecular Oncology and Department of Radiation Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of General Surgery Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghai 200080China Department of General Surgery Zhongshan HospitalFudan UniversityShanghai 200032China Department of Dermatology University of California San DiegoSan DiegoCA 92093USA Department of Oncology Mayo ClinicRochesterMN 55905USA

The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor progression.AMPK is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy stores.Previous studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic cancer.In this study,we report that AMPK is also highly sensitive to extracellular matrix(ecm)stiffness.We found that AMPK is activated in cells when cultured under low ecm stiffness conditions and is functionally required for the metabolic switch induced by ecm stiffness.This regulation of AMPK requires the Hippo kinases but not LKB1/CaMKKp.Hippo kinases directly phosphorylate AMPKa at Thr172 to activate AMPK at low ecm stiffness.Furthermore,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ecm stiffness and is associated with a poor survival outcome.The activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC growth.Together,these findings establish a novel model for AMPK regulation by the mechanical properties of ecms and provide a rationale for simultaneously targeting the ecm stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.

关键词： AMPKactivity Cellularmetabolic switch ecm stiffness Hippokinase signaling Pancreaticductal adenocarcinoma

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Decellularized extracellular matrix as scaffold for cancer organoid cultures of colorectal peritoneal metastases

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Journal of Molecular Cell Biology 2022年第11期14卷 36-49页

作者： Luca Varinelli Marcello Guaglio Silvia Brich Susanna Zanutto Antonino Belfiore Federica Zanardi Fabio Iannelli Amanda Oldani Elisa Costa Matteo Chighizola Ewelina Lorenc Simone P.Minardi Stefano Fortuzzi Martina Filugelli Giovanna Garzone Federica Pisati Manuela Vecchi Giancarlo Pruneri Shigeki Kusamura Dario Baratti Laura Cattaneo Dario Parazzoli Alessandro Podestà Massimo Milione Marcello Deraco Marco A.Pierotti Manuela Gariboldi Department of Research Fondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly Peritoneal Surface Malignancies Unit Colon and Rectal SurgeryFondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly Department of Pathology and Laboratory Medicine Clinical Research lABoratory(CRAB)Fondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly Bioinformatics Core Unit IFOM ETSThe AIRC Institute of Molecular Oncologyvia Adamello 1620139 MilanItaly Imaging Technological Development Unit IFOM ETSThe AIRC Institute of Molecular Oncologyvia Adamello 1620139 MilanItaly C.I.Ma.I.Na.and Dipartimento di Fisica‘Aldo Pontremoli’ Universitàdegli Studi di Milanovia G.Celoria 1620133 MilanItaly Cogentech Ltd Benefit Corporation with a Sole Shareholder via Adamello 1620139 MilanItaly Pathology and Laboratory Medicine Department Fondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly

Peritoneal metastases (PM) from colorectal cancer (CRC) are associated with poor survival. The extracellular matrix (ecm) plays a fundamental role in modulating the homing of CRC metastases to the peritoneum. The mechanisms underlying the interactions between metastatic cells and the ecm, however, remain poorly understood, and the number of in vitro models available for the study of the peritoneal metastatic process is limited. Here, we show that decellularized ecm of the peritoneal cavity allows the growth of organoids obtained from PM, favoring the development of three-dimensional (3D) nodules that maintain the characteristics of in vivo PM. Organoids preferentially grow on scaffolds obtained from neoplastic peritoneum, which are characterized by greater stiffness than normal scaffolds. A gene expression analysis of organoids grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. An impact of the ecm on the response to standard chemotherapy treatment for PM was also observed. The ex vivo 3D model, obtained by combining patient-derived decellularized ecm with organoids to mimic the metastatic niche, could be an innovative tool to develop new therapeutic strategies in a biologically relevant context to personalize treatments.

关键词： colorectal cancer peritoneal metastasis organoids extracellular matrix(ecm) decellularized extracellular matrix engineered disease model ecm stiffness

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