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 mech...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.展开更多
Postnatal mammalian cardiomyocytes(CMs)rapidly lose proliferative capacity and exit the cell cycle to undergo further differentiation and maturation.Cell cycle activation has been a major strategy to stimulate postnat...Postnatal mammalian cardiomyocytes(CMs)rapidly lose proliferative capacity and exit the cell cycle to undergo further differentiation and maturation.Cell cycle activation has been a major strategy to stimulate postnatal CM proliferation,albeit achieving modest effects.One impediment is that postnatal CMs may need to undergo dedifferentiation before proliferation,if not simultaneously.Here,we report that overexpression of Hdac7 in neonatal mouse CMs results in significant CM dedifferentiation and proliferation.Mechanistically,we showthat histone deacetylase7(HDAC7)-mediatedCM proliferation is contingent on dedifferentiation,which is accomplished by suppressing myocyte enhancefactor2(MEF2).Hdac7overexpression in CM shifts the chromatin state from binding with MEF2,which favors the transcriptional program toward differentiation,to binding with AP-1,which favors the transcriptional program toward proliferation.Furthermore,we found that HDAC7 interacts with minichromosome maintenance complex components to initiate cell cycleprogression.Ourfindings revealthat HDAC7 promotes CM proliferation byits dual action on CM dedifferentiation and proliferation,uncovering a potential new strategy for heart regeneration/repair.展开更多
基金supported by an Italian law that allows taxpayers to allocate 0.5%of their tax to a research institution of their choice,by EU Horizon 2020 Marie Skłodowska-Curie programme 812772(project Phys2BioMed)by FET Open 801126(project EDIT).
文摘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.
基金supported by the National Heart,Lung,and Blood Institute R01 grant(HL153406).
文摘Postnatal mammalian cardiomyocytes(CMs)rapidly lose proliferative capacity and exit the cell cycle to undergo further differentiation and maturation.Cell cycle activation has been a major strategy to stimulate postnatal CM proliferation,albeit achieving modest effects.One impediment is that postnatal CMs may need to undergo dedifferentiation before proliferation,if not simultaneously.Here,we report that overexpression of Hdac7 in neonatal mouse CMs results in significant CM dedifferentiation and proliferation.Mechanistically,we showthat histone deacetylase7(HDAC7)-mediatedCM proliferation is contingent on dedifferentiation,which is accomplished by suppressing myocyte enhancefactor2(MEF2).Hdac7overexpression in CM shifts the chromatin state from binding with MEF2,which favors the transcriptional program toward differentiation,to binding with AP-1,which favors the transcriptional program toward proliferation.Furthermore,we found that HDAC7 interacts with minichromosome maintenance complex components to initiate cell cycleprogression.Ourfindings revealthat HDAC7 promotes CM proliferation byits dual action on CM dedifferentiation and proliferation,uncovering a potential new strategy for heart regeneration/repair.
