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LATS1/2–integrin axis confers tumor-generated forces that activate neighboring fibroblasts

ABSTRACT: LATS1/2–integrin axis confers tumor-generated forces that activate neighboring fibroblasts

PROVIDER: PRJNA1189170 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31439061_1.fastq.gz	Fastqsanger.gz
	SRR31439061_2.fastq.gz	Fastqsanger.gz
	SRR31439062_1.fastq.gz	Fastqsanger.gz
	SRR31439062_2.fastq.gz	Fastqsanger.gz
	SRR31439063_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

LATS1/2–integrin axis confers tumor-generated forces that activate neighboring fibroblasts

Project description:Tumors generate various forces during growth and progression, which, in turn, promote tumor development. Although fibroblasts are considered the primary force generators in the tumor microenvironment, recent studies have shown that cancer cells also generate considerable tensile force. However, the role of these forces in the tumor microenvironment and the pathways regulating this process remain largely unknown. Here, we demonstrate that the Hippo pathway kinases LATS1/2 in cancer cells are essential for collective force generation and fibroblast activation via extracellular matrix-mediated cell–cell interactions. In murine breast cancer 4T1 spheroids, deletion of LATS1/2 dampens force generation and disrupts the reorganization of surrounding collagen matrix. The LATS1/2-mediated mechanical forces of the tumor are required for fibroblast activation and differentiation into mechanoresponsive fibroblasts. Mechanistically, LATS1/2 regulate tumor force generation through the expression of the collagen receptor integrins. Our findings not only identify the Hippo pathway as a critical regulator of tumor force generation, but also suggest potential strategies for targeting the Hippo pathway in cancer therapy from the mechanobiological perspective, offering new avenues in the fight against cancer.

2025-05-22 | GSE282581 | GEO

Genome-wide analysis of livers of control and Lats1/2 deficient neonatal mice [Microarray expression]

Project description:Lats1-/-;Lats2fl/fl;Alb-Cre pups and control pups were sacrificed at 1 day after birth Total mRNA obtained from livers in control and Lats1/2 deficient neonatal mice

2016-06-29 | E-GEOD-71872 | biostudies-arrayexpress

Cell-generated forces contribute to bottleneck during somatic cell reprogramming

Project description:Our study investigates the effects of cell adhesion and traction forces on reprogramming by utilizing a human fibroblast cell line (hiF-T) that can be reprogrammed by activating the expression of an OKSM (OCT4, KLF4, SOX2, C-MYC) gene cassette through the addition of doxycycline. We performed RNA interference experiments on 103 genes found in the ‘adhesome’ (encoding integrins, cadherins, and associated proteins) that are expressed and dynamically regulated (6-fold or more) across the reprogramming timeline. The impact of each shRNA on iPSC generation efficiency was assessed by immunostaining for TRA-1-60, a known pluripotency marker. From this RNAi screen, we identified the SHROOM3 knockdown as a potent reprogramming efficiency enhancer and generated RNA-seq timelines throughout reprogramming with or without shRNAs targeting SHROOM3 or a LacZ control. Gene co-expression network analysis highlights the existence of a critical state transition regulated through a SHROOM3-SRF signaling axis during late reprogramming, which coincides with cell-mediated force generation. Taken together, our data suggest that adhesome gene expression acts as a significant impediment to somatic cell reprogramming through the activation of mechano-signaling pathways associated with cell traction forces. These results provide important new insights into the role of cell adhesion and force generation during reprogramming to pluripotency and somatic cell fate transitions more broadly.

2023-04-10 | GSE148580 | GEO

Defining single molecular forces required to activate integrin and notch signaling.

Project description:Cell-cell and cell-matrix mechanical interactions through membrane receptors direct a wide range of cellular functions and orchestrate the development of multicellular organisms. To define the single molecular forces required to activate signaling through a ligand-receptor bond, we developed the tension gauge tether (TGT) approach in which the ligand is immobilized to a surface through a rupturable tether before receptor engagement. TGT serves as an autonomous gauge to restrict the receptor-ligand tension. Using a range of tethers with tunable tension tolerances, we show that cells apply a universal peak tension of about 40 piconewtons (pN) to single integrin-ligand bonds during initial adhesion. We find that less than 12 pN is required to activate Notch receptors. TGT can also provide a defined molecular mechanical cue to regulate cellular functions.

| S-EPMC3710701 | biostudies-literature

Allometric tissue-scale forces activate mechanoresponsive immune cells to determine pathological foreign body response to biomedical implants

Project description:Allometric tissue-scale forces at the implant-tissue interface drive pathological foreign body response.

2023-06-05 | GSE227908 | GEO

Genome-wide analysis of gene expression using in vitro cultured control and Lats1/2 deficient hepatoblasts [RNA-Seq]

Project description:RNA-sequencing results with in vitro cultured control and Lats1/2 deficient hepatoblasts, in vitro differentiated control and Lats1/2 deficient hepatocytes and biliary epithelial cells To investigate changes in gene expression by loss of Lats1 and Lats2 during hepatocyte or biliary epithelial cell differentiation, we performed multiplex RNA-sequecing with in vitro cultured hepatoblasts, in vitro differentiated hepatocytes and biliary epithelial cells

2016-06-29 | E-GEOD-71873 | biostudies-arrayexpress

Integrin-generated forces lead to streptavidin-biotin unbinding in cellular adhesions.

Project description:The interplay between chemical and mechanical signals plays an important role in cell biology, and integrin receptors are the primary molecules involved in sensing and transducing external mechanical cues. We used integrin-specific probes in molecular tension fluorescence microscopy to investigate the pN forces exerted by integrin receptors in living cells. The molecular tension fluorescence microscopy probe consisted of a cyclic Arg-Gly-Asp-D-Phe-Lys(Cys) (cRGDfK(C)) peptide tethered to the terminus of a polyethylene glycol polymer that was attached to a surface through streptavidin-biotin linkage. A fluorescence resonance energy transfer mechanism was used to visualize tension-driven extension of the polymer. Surprisingly, we found that integrin receptors dissociate streptavidin-biotin tethered ligands in focal adhesions within 60 min of cell seeding. Although streptavidin-biotin binding affinity is described as the strongest noncovalent bond in nature, and is ~10(6) - 10(8) times larger than that of integrin-RGD affinity, our results suggest that individual integrin-ligand complexes undergo a marked enhancement in stability when the receptor assembles in the cell membrane. Based on the observation of streptavidin-biotin unbinding, we also conclude that the magnitude of integrin-ligand tension in focal adhesions can reach values that are at least 10 fold larger than was previously estimated using traction force microscopy-based methods.

| S-EPMC3976516 | biostudies-literature

Cell-generated forces contribute to bottleneck during somatic cell reprogramming

Project description:Cell-generated forces contribute to bottleneck during somatic cell reprogramming

| PRJNA625072 | ENA

Adhesion-mediated mechanosignaling forces mitohormesis

Project description:Adhesion-mediated mechanosignaling forces mitohormesis

| PRJNA718277 | ENA

The Hippo pathway kinase LATS1 scaffolds Beclin1 in autophagy regulation in hepatocellular carcinoma

Project description:Autophagy perturbation represents an emerging therapeutic strategy in cancer. The mammalian Hippo pathway is an evolutionary conserved tumor suppressive network, where the kinases LATS1/2 phosphorylate and inactivate oncogenic YAP/TAZ. Here, we demonstrated a pro-survival role of LATS1, but not LATS2, in hepatocellular carcinoma cells in response to sorafenib, a standard care of advanced HCC. Transcriptomic analysis revealed a restrictive role of LATS1 in autophagy regulation in HCC cells. Further, we found that the autophagy regulation by LATS1 was independent of its kinase activity. Instead, LATS1 stabilized autophagy core-machinery component Beclin 1 via promoting a non-canonical form of K27-linked ubiquitination, and consequently, inactive Beclin 1 self-dimer, in a E3 ligase NEDD4 dependent manner. Our study highlights a functional diversity between LATS1 and LATS2 and uncovers a scaffolding role of LATS1 in mediating a cross-talk between Hippo signalling and autophagy in HCC and therapy response.

2019-11-13 | GSE117116 | GEO

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