Biophysical and Epigenetic Regulation of Cancer Stemness, Invasiveness, and Immune Action

Abstract

Purpose of Review The tumor microenvironment (TME) is an amalgam of multiple dysregulated biophysical cues that can alter cellular behavior through mechanotransductive signaling and epigenetic modifications. Through this review, we seek to characterize the extent of biophysical and epigenetic regulation of cancer stemness and tumor-associated immune cells in order to identify ideal targets for cancer therapy. Recent Findings Recent studies have identified cancer stemness and immune action as significant contributors to neoplastic disease, due to their susceptibility to microenvironmental influences. Matrix stiffening, altered vasculature, and resultant hypoxia within the TME can influence cancer stem cell (CSC) and immune cell behavior, as well as alter the epigenetic landscapes involved in cancer development. Summary This review highlights the importance of aberrant biophysical cues in driving cancer progression through altered behavior of CSCs and immune cells, which in turn sustains further biophysical dysregulation. We examine current and potential therapeutic approaches that break this self-sustaining cycle of disease progression by targeting the presented biophysical and epigenetic signatures of cancer. We also summarize strategies including the normalization of the TME, targeted drug delivery, and inhibition of cancer-enabling epigenetic players.

A Hierarchical Mechanotransduction System: From Macro to Micro

“…[ 374 ] Of note, the impact between mechanotransduction and nonmutational epigenetic reprogramming is currently debated. Emerging evidence has proposed that cell could sense and respond to the surroundings by transmitting mechanical stimuli into biochemical signals, and thus affect epigenetic states, [ 375 ] such as DNA/histone methylation, [ 376 ] histone acetylation, and microRNA expression, [ 377 ] whose dysregulation are involved in disease progression. [ 378 , 379 , 380 ] We believe that an increasing number of prospective studies will fill the gap between mechanotransduction and non‐mutational epigenetics.…”

Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma

“…Stromal expression of DDR1 has also been shown to promote the growth of tumors harboring WNT-activated phenotype ( 138 ), and collagens have been widely documented as prognostic markers in colon cancer progression to metastasis ( 139 – 146 ). ECM deposition poses a challenge to immune cell infiltration in tumors and impairs treatment efficacy, and ECM signaling has emerged as a potential target for cancer therapy ( 147 – 151 ). Moreover, the effects of conventional radiotherapy (RT) on tumor stroma and ECM composition with exacerbating tumor-promoting phenotype in a KRAS-dependent manner in GBM has been documented and reviewed ( 106 , 152 ).…”

Targeting epigenetic alterations in cancer stem cells

“…Of note, altered biophysical forces derived from surrounding tumor microenvironment (TME) could promote EMT process and cancer stemness through the alteration of epigenetic signatures. Accordingly, epigenetic enzymes such as histone modifiers have been reported to be regulated by an altered mechanotransduction ( Veerasubramanian et al, 2020 ). The origin and maintenance of CSCs is finely regulated by the mechanotransduction proprieties of extracellular matrix (ECM) through a great variety of cell surface receptors and the physical interaction of CSCs with their surrounding ECMs.…”