Extracellular-matrix mechanics regulate cellular metabolism: A ninja warrior behind mechano-chemo signaling crosstalk

Liao, Xiaoyu; Li, Xin; Li, Rui

doi:10.1007/s11154-022-09768-z

Cited by 11 publications

(5 citation statements)

References 108 publications

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“…SDC4 is a well-recognized mechanosensor with a pivotal role in mechanotransduction at the level of the cell-matrix interface [ 18 ]. A growing body of evidence argues for a role of mechanotransduction signaling pathways in metabolic dysfunction [ 38 , 39 ]. To this end, we previously reported that HFD-fed female mice lacking functional SDC4 had increased adiposity and macrophage infiltration in the visceral adipose tissue than WT mice [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Syndecan-4 as a genetic determinant of the metabolic syndrome

Crocco

Vecchie

Sreejit

et al. 2023

Diabetol Metab Syndr

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Background Syndecan-4 (SDC4) is a member of the heparan sulfate proteoglycan family of cell-surface receptors. We and others previously reported that variation in the SDC4 gene was associated with several components of the metabolic syndrome, including intra-abdominal fat, fasting glucose and triglyceride levels, and hypertension, in human cohorts. Additionally, we demonstrated that high fat diet (HFD)-induced obese female mice with a Sdc4 genetic deletion had higher visceral adiposity and a worse metabolic profile than control mice. Here, we aimed to first investigate whether the mouse Sdc4 null mutation impacts metabolic phenotypes in a sex- and diet-dependent manner. We then tested whether SDC4 polymorphisms are related to the metabolic syndrome (MetS) in humans. Methods For the mouse experiment, Sdc4-deficient (Sdc4−/−) and wild-type (WT) mice were treated with 14-weeks of low-fat diet (LFD). Body composition, energy balance, and selected metabolic phenotypes were assessed. For the human genetic study, we used logistic regression models to test 11 SDC4 SNPs for association with the MetS and its components in a cohort of 274 (113 with MetS) elderly subjects from southern Italy. Results Following the dietary intervention in mice, we observed that the effects of the Sdc4 null mutation on several phenotypes were different from those previously reported in the mice kept on an HFD. Nonetheless, LFD-fed female Sdc4−/− mice, but not males, displayed higher levels of triglycerides and lower insulin sensitivity at fasting than WT mice, as seen earlier in the HFD conditions. In the parallel human study, we found that carriers of SDC4 rs2228384 allele C and rs2072785 allele T had reduced risk of MetS. The opposite was true for carriers of the SDC4 rs1981429 allele G. Additionally, the SNPs were found related to fasting triglyceride levels and triglyceride glucose (TyG) index, a reliable indicator of insulin resistance, with sex-stratified analysis detecting the association of rs1981429 with these phenotypes only in females. Conclusions Altogether, our results suggest that SDC4 is an evolutionary conserved genetic determinant of MetS and that its genetic variation is associated with fasting triglyceride levels in a female-specific manner.

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Section: Discussionmentioning

confidence: 99%

Syndecan-4 as a genetic determinant of the metabolic syndrome

Crocco

Vecchie

Sreejit

et al. 2023

Diabetol Metab Syndr

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“…The matrisome genes are relatively numerous, and the seminal work by Richard Hynes, Alexandra Naba, and colleagues [21,22] recognized more than a thousand such proteins in the human genome, divided into six categories (ECM glycoproteins, collagens, proteoglycans, ECM-affiliated proteins, ECM regulators, and secreted factors). The ECM and the matrisome proteins are involved in almost every feature and process in cancer cells and tissues [23], including proliferation, survival, motility, migration, invasion, epithelial-to-mesenchymal transition (EMT) [24,25], metastasis formation [26], gene expression, response to therapies [2,[27][28][29][30], metabolism [31,32], angiogenesis [33,34], and immune system escape [35]. Given that the ECM is the first frontier of the cell towards its surroundings, its involvement in the mentioned processes and the fact that the cells actively respond to their environment are not surprising.…”

Section: The Role Of Ecm Proteins In Prostate Cancermentioning

confidence: 99%

The Potential of Extracellular Matrix- and Integrin Adhesion Complex-Related Molecules for Prostate Cancer Biomarker Discovery

Samaržija

2023

Biomedicines

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Prostate cancer is among the top five cancer types according to incidence and mortality. One of the main obstacles in prostate cancer management is the inability to foresee its course, which ranges from slow growth throughout years that requires minimum or no intervention to highly aggressive disease that spreads quickly and resists treatment. Therefore, it is not surprising that numerous studies have attempted to find biomarkers of prostate cancer occurrence, risk stratification, therapy response, and patient outcome. However, only a few prostate cancer biomarkers are used in clinics, which shows how difficult it is to find a novel biomarker. Cell adhesion to the extracellular matrix (ECM) through integrins is among the essential processes that govern its fate. Upon activation and ligation, integrins form multi-protein intracellular structures called integrin adhesion complexes (IACs). In this review article, the focus is put on the biomarker potential of the ECM- and IAC-related molecules stemming from both body fluids and prostate cancer tissue. The processes that they are involved in, such as tumor stiffening, bone turnover, and communication via exosomes, and their biomarker potential are also reviewed.

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“…[1][2][3][4][5] Due to that tissue fibrosis and ECM stiffening associate with poor tumor prognosis, [6,7] changing ECM rigidity via collagen depletion or lysyl oxidase (LOX) inhibition, or pharmaceutically altering cellular mechanotransduction have been promising options for cancer therapy. [8][9][10] However, tumor cells also exhibit resistance to anoikis-the ECM detachment-induced cell death. How tumor cells manage to gain growth advantage on stiff substrate while resist cell death upon matrix detachment remain enigmatic.…”

Section: Introductionmentioning

confidence: 99%

mTORC1 Mediates Biphasic Mechano‐Response to Orchestrate Adhesion‐Dependent Cell Growth and Anoikis Resistance

Zhang,

Wang,

Zhen

et al. 2023

Advanced Science

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Cells constantly sense and respond to not only biochemical but also biomechanical changes in their microenvironment, demanding for dynamic metabolic adaptation. ECM stiffening is a hallmark of cancer aggressiveness, while survival under substrate detachment also associates with poor prognosis. Mechanisms underlying this, non‐linear mechano‐response of tumor cells may reveal potential double‐hit targets for cancers. Here, an integrin‐GSK3β‐FTO‐mTOR axis is reported, that can integrate stiffness sensing to ensure both the growth advantage endowed by rigid substrate and cell death resistance under matrix detachment. It is demonstrated that substrate stiffening can activate mTORC1 and elevate mTOR level through integrins and GSK3β‐FTO mediated mRNA m6A modification, promoting anabolic metabolism. Inhibition of this axis upon ECM detachment enhances autophagy, which in turn conveys resilience of tumor cells to anoikis, as it is demonstrated in human breast ductal carcinoma in situ (DCIS) and mice malignant ascites. Collectively, these results highlight the biphasic mechano‐regulation of cellular metabolism, with implications in tumor growth under stiffened conditions such as fibrosis, as well as in anoikis‐resistance during cancer metastasis.

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Extracellular-matrix mechanics regulate cellular metabolism: A ninja warrior behind mechano-chemo signaling crosstalk

Cited by 11 publications

References 108 publications

Syndecan-4 as a genetic determinant of the metabolic syndrome

Syndecan-4 as a genetic determinant of the metabolic syndrome

The Potential of Extracellular Matrix- and Integrin Adhesion Complex-Related Molecules for Prostate Cancer Biomarker Discovery

mTORC1 Mediates Biphasic Mechano‐Response to Orchestrate Adhesion‐Dependent Cell Growth and Anoikis Resistance

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