Fibrin Stiffness Mediates Dormancy of Tumor-Repopulating Cells via a Cdc42-Driven Tet2 Epigenetic Program

Abstract

Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here, we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2. Tet2 epigenetically activated cell-cycle-inhibiting genes p21 and p27 to induce dormancy, but also caused downregulation of integrin β3 to maintain dormancy. This stiffness-mediated dormancy was recapitulated in mouse models for both murine and primary human melanoma TRCs. These data identify an epigenetic program directed by mechanics, which drives highly tumorigenic TRCs to enter dormancy in a stiff mechanical environment. A mechanics-directed epigenetic program enables tumor-repopulating cells to enter dormancy in a stiff mechanical environment. .

Immobilization rapidly selects for chemoresistant ovarian cancer cells with enhanced ability to enter dormancy

“…This demonstration of encapsulation in a stiff biomaterial prompting cell cycle exit recapitulates previous studies where gels derived from organic materials, such as collagen (Fang et al, 2016) or fibrin (Liu et al, 2018), showed increasing stiffness results in slowed cell growth and metabolism. Here, the silica gels are advantageous as they do not allow for subsequent growth or division once cells are immobilized, providing a harsh environment that causes most cells to quickly die.…”

Extracellular matrix (ECM) stiffness and degradation as cancer drivers

“…HA accumulation in central parts is for resistance of tumors to compressive stresses. In the periphery of tumors, collagen and fibronectin are accumulated and developed tensile stresses . Collagen is the most frequent ECM scaffolding protein within the stroma that undergoes metabolic deregulation in cancer .…”

Lymphocyte mechanotransduction: The regulatory role of cytoskeletal dynamics in signaling cascades and effector functions

“…It has been recognized that physical cues from the environment transduce biochemical pathways that impact a wide range of fateful decisions in different cells . The mechanisms of mechanotransduction, the conversion of physical forces into biochemical signals that might impact cell decision and cell fate, and mechanosensation, the effect of extracellular substrate rigidity on cellular functions, were documented in several cell types and tissues.…”

“…It has been recognized that physical cues from the environment transduce biochemical pathways that impact a wide range of fateful decisions in different cells. [1][2][3] The mechanisms of mechanotransduction, the conversion of physical forces into biochemical signals that might impact cell decision and cell fate, and mechanosensation, the effect of extracellular substrate rigidity on cellular functions, were documented in several cell types and tissues. Examples include studies in which force was exerted on kidney epithelial cells, inducing reentry into the cell cycle and DNA replication, 1 and studies that used substrates with different rigidities to induce muscle stem cell regeneration, or to induce dormancy in neoplastic transformed cells.…”

“…Examples include studies in which force was exerted on kidney epithelial cells, inducing reentry into the cell cycle and DNA replication, 1 and studies that used substrates with different rigidities to induce muscle stem cell regeneration, or to induce dormancy in neoplastic transformed cells. 2,3 The central regulator and mediator of both cellular mechanosensa-can induce morphologic changes in the cytoskeleton, and in the cell, and produce specific structures and different cytoskeletal dynamics, depending on the environment. 5 As we will describe in this review, the cytoskeleton plays a pivotal role in mediating forces transduced to mechanosensitive receptors such as the T cell and B cell receptors (TCRs and BCRs), and on integrin orientation and affinity.…”