Biomechanical properties of chromatin in cancer and normal cells

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Chromatin composition and organization define genome function in eukaryotes. Aside from its transcriptional influences, chromatin also contributes to the mechanical stiffness of the nucleus, a sensor governing cellular mechanoresponses critical for tumor adaptation to the microenvironment. A fundamental question remains: how does chromatin respond to mechanical forces, in the context of tumor-stroma interactions? Glioblastoma is one of the most malignant and lethal cancers, with less than two years of median survival and highly deregulated chromatin composition. Moreover, recapitulating the complex tumor microenvironment in vitro poses a major challenge for novel therapy development. Here, we utilize 3D bio-printed glioblastoma tissues mimicking the tumor microenvironment in vivo, and traditional 2D culture to study the mechanical properties and chromatin mechanoresponses using atomic force microscopy, immunofluorescence staining, and other biochemical assays. Over the last fiscal year, we found that treatment of specific chemotherapy drugs differentially alters tissue stiffness, potentially leading to altered chromatin composition and affecting tumor killing outcomes. Specifically, the only approved first-line chemotherapy drug for glioblastoma, temozolomide, surprisingly promotes endothelial network growth and stiffens tumor stroma, leading to increased proliferative subpopulation of glioblastoma cells in the tumor. On the contrary, another promising chemotherapy drug, regorafenib, softens tumor stroma, leading to decreased proliferative subpopulation of glioblastoma cells in the tumor. Our study aims to provide the first model of the interactions between chromatin mechanoresponses, tumor microenvironment, and drug response in glioblastoma. Targeting chromatin mechanoresponse pathways may lead to new therapeutic agents in the fight against the currently incurable glioblastoma.