3D matrix promotes cell dedifferentiation into colorectal cancer stem cells via integrin/cytoskeleton/glycolysis signaling

Abstract

The potential for tumor occurrence triggered by cancer stem cells (CSCs) has emerged as a significant challenge for human colorectal cancer therapy. However, the underlying mechanism of CSC development remains controversial. Our study provided evidence that the bulk of tumor cells could dedifferentiate to CSCs and reacquire CSC‐like phenotypes if cultured in the presence of extracellular matrix reagents, such as Matrigel and fibrin gels. In these 3D gels, CD133− colorectal cancer cells can regain tumorigenic potential and stem‐like phenotypes. Mechanistically, the 3D extracellular matrix could mediate cytoskeletal F‐actin bundling through biomechanical force associated receptors integrin β1 (ITGB1), contributing to the release of E3 ligase tripartite motif protein 11 (TRIM11) from cytoskeleton and degradation of the glycolytic rate‐limiting enzyme phosphofructokinase (PFK). Consequently, PFK inhibition resulted in enhanced glycolysis and upregulation of hypoxia‐inducible factor 1 (HIF1α), thereby promoting the reprogramming of stem cell transcription factors and facilitating tumor progression in patients. This study provided novel insights into the role of the extracellular matrix in the regulation of CSC dedifferentiation in a cytoskeleton/glycolysis‐dependent manner.

3D environment promotes persistent changes in lamin B1 distribution, the biomechanical signature of the nucleus, and adaptative survival and migratory functions

“…One of the key cellular regulators of nuclear dysmorphia, lamin redistribution and chromatin changes is actomyosin contractility (49). In addition, the actin cytoskeleton connects the cell receptors to the nuclear envelope and leads to the transmission of external stimuli, nuclear translocation, and other intracellular pathways that control the mechanical response of the nucleus (50). Apart from their role in the cytoplasm, the actomyosin machinery (actin, myosins, and associated proteins) can be recruited into the nucleus interacting with polymerases and transcription factors regulating multiple functions, including DNA repair, transcription, and cell cycle progression (27,51,52).…”

Integrinβ-1 in disorders and cancers: molecular mechanisms and therapeutic targets

“…In LC, ITGB1-actin-MT1-MMPs/cofilin/F-actin signaling axis promotes cancer cell motility in an acidic microenvironment [91]. In CRC, CD133 − CRC cells can restore tumorigenic potential and stem cell-like characteristics [92]. The three-dimensional (3-d) ECM can mediate cytoskeletal F-actin bundling via biomechanical pressures linked with the receptor ITGB1, causing the cytoskeleton to release the E3 ligase TRIM11 and degrade the glycolytic rate-limiting enzyme phosphatidylinositol (PFK) [92].…”

“…In CRC, CD133 − CRC cells can restore tumorigenic potential and stem cell-like characteristics [92]. The three-dimensional (3-d) ECM can mediate cytoskeletal F-actin bundling via biomechanical pressures linked with the receptor ITGB1, causing the cytoskeleton to release the E3 ligase TRIM11 and degrade the glycolytic rate-limiting enzyme phosphatidylinositol (PFK) [92]. As a result, PFK inhibition increased glycolysis and upregulated HIF1α, promoting the reprogramming of stem cell transcription factors and aided tumor growth in patients [92].…”

“…The three-dimensional (3-d) ECM can mediate cytoskeletal F-actin bundling via biomechanical pressures linked with the receptor ITGB1, causing the cytoskeleton to release the E3 ligase TRIM11 and degrade the glycolytic rate-limiting enzyme phosphatidylinositol (PFK) [92]. As a result, PFK inhibition increased glycolysis and upregulated HIF1α, promoting the reprogramming of stem cell transcription factors and aided tumor growth in patients [92]. In addition, alcohol encourages the interaction between LAMC2 and ITGB1, increasing p-FAK/FAK, snail, fibronectin, N-cadherin, and SATB1 while decreasing E-cadherin in the alcohol group compared to the non-alcohol group [93].…”

“…TN-C, a ligand of ITGB1 and ITGB3, is produced by breast cancer cells to encourage CSC selfrenewal and to improve their capacity to initiate metastasis [84]. In CD133 − CRC cells, ITGB1 facilitates the reprogramming of stem cell transcription factors and the recovery of tumorigenic potential and stem cell-like characteristics [92]. The downregulation of SDC1 synergistically promoted activation of ITGB1 and FAK, increasing the invasiveness of the signal and the properties of CSCs [37].…”