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Peristaltic forces drive tumor cell invasion in colorectal cancer [bulk RNA-seq]

ABSTRACT: Mechanical forces are known to influence the progression of cancer, however, the impact of naturally occurring physical forces remains less well understood. With the advent of organ-on-chip (OOC) technology, preclinical models can now incorporate human-relevant physiological forces and allow for more precise investigation of their effects. In this study, we explore how the peristaltic motions of the gut influence the early metastatic spread of colorectal cancer (CRC). Specifically, we use a CRC OOC model consisting of tumor epithelial and endothelial channels separated by a porous membrane to investigate, through live cell imaging and ‘omics-based approaches, how peristaltic compressions enhance the invasiveness of colorectal cancer cells. scRNA-seq analysis revealed that invaded tumor cells exhibited significantly higher expression of mechanosensitive genes compared to non-invaded cells. Among the enriched genes was the mechanosensitive calcium ion channel, PIEZO1. Knockdown of PIEZO1 disrupted YAP1-mediated mechanotransduction and reduced invasive capability. In contrast, exposure to peristaltic contractions enhanced invasiveness. Analysis of publicly available datasets confirmed that elevated tumor mechanosensitive gene expression is associated with poorer clinical outcomes. These findings reveal how physiological mechanical forces drive the invasive behavior of mechanosensitive CRC tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE311632 | GEO | 2026/06/30

REPOSITORIES: GEO

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Peristaltic forces drive tumor cell invasion in colorectal cancer [scRNA-seq]

Project description:Mechanical forces are known to influence the progression of cancer, however, the impact of naturally occurring physical forces remains less well understood. With the advent of organ-on-chip (OOC) technology, preclinical models can now incorporate human-relevant physiological forces and allow for more precise investigation of their effects. In this study, we explore how the peristaltic motions of the gut influence the early metastatic spread of colorectal cancer (CRC). Specifically, we use a CRC OOC model consisting of tumor epithelial and endothelial channels separated by a porous membrane to investigate, through live cell imaging and ‘omics-based approaches, how peristaltic compressions enhance the invasiveness of colorectal cancer cells. scRNA-seq analysis revealed that invaded tumor cells exhibited significantly higher expression of mechanosensitive genes compared to non-invaded cells. Among the enriched genes was the mechanosensitive calcium ion channel, PIEZO1. Knockdown of PIEZO1 disrupted YAP1-mediated mechanotransduction and reduced invasive capability. In contrast, exposure to peristaltic contractions enhanced invasiveness. Analysis of publicly available datasets confirmed that elevated tumor mechanosensitive gene expression is associated with poorer clinical outcomes. These findings reveal how physiological mechanical forces drive the invasive behavior of mechanosensitive CRC tumors.

2026-06-30 | GSE311338 | GEO

Targeting Piezo1 Unleashes Innate Immunity Against Cancer and Infectious Disease

Project description:Piezo1 is a mechanosensitive ion channel that has gained recognition for its role in regulating diverse physiological processes. However, the influence of Piezo1 in inflammatory disease, including infection and tumor-immunity, is not well-studied. We postulated that Piezo1 links physical forces to immune regulation in myeloid cells. We discovered signal transduction via Piezo1 in myeloid cells and established this channel as the primary sensor of mechanical stress in these cells. Global inhibition of Piezo1 was protective against both cancer and septic shock and resulted in a diminution in suppressive myeloid cells. Moreover, deletion of Piezo1 in myeloid cells protected against cancer and increased survival in poly-microbial sepsis. Mechanistically, we show that mechanical stimulation promotes Piezo1-dependent myeloid cell expansion by suppressing Rb. We further show Piezo1-mediated silencing of Rb is regulated via upregulation of HDAC2. Collectively, our work uncovers Piezo1 as a targetable immune checkpoint that drives immune-suppressive myelopoiesis in cancer and infectious disease.

2020-08-21 | GSE155340 | GEO

RNA-seq analysis of Piezo1-deficient muscle satellite cells

Project description:Muscle satellite cells (MuSCs), skeletal muscle-resident stem cells, are crucial for regeneration of myofibers. Mechanical cues are thought to be important for activation and proliferation of muscle satellite cells, but the molecular entity that senses biophysical forces in MuSCs remains to be elucidated. In this study, we identified PIEZO1, a mechanosensitive ion channel that is activated by membrane tension, as a critical determinant for myofiber regeneration. We investigated gene profiles of Piezo1-deficient MuSCs to understand the role of PIEZO1 during myogenesis. Our results suggest that PIEZO1 governs the cytoskeletal reorganization to regulate cellular events in MuSCs (i.e., activation, cell-division, and proliferation) during skeletal muscle regeneration.

2022-11-18 | GSE217417 | GEO

Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk

Project description:Wolff’s law and the Utah Paradigm of skeletal physiology state that bone architecture adapts to mechanical loads. These models predict the existence of a mechanostat that links strain induced by mechanical forces to skeletal remodeling. However, how the mechanostat influences bone remodeling remains elusive. Here, we find that Piezo1 deficiency in osteoblastic cells leads to loss of bone mass and spontaneous fractures with increased bone resorption. Furthermore, Piezo1-deficient mice are resistant to further bone loss and bone resorption induced by hind limb unloading, demonstrating that PIEZO1 can affect osteoblast-osteoclast crosstalk in response to mechanical forces. At the mechanistic level, in response to mechanical loads, PIEZO1 in osteoblastic cells controls the YAP-dependent expression of type II and IX collagens. In turn, these collagen isoforms regulate osteoclast differentiation. Taken together, our data identify PIEZO1 as the major skeletal mechanosensor that tunes bone homeostasis.

2019-12-07 | GSE135282 | GEO

Study on the mechanisms of Piezo1-lars2 signal path mediating the mechanical loading on endochondral ossification process of fracture healing

Project description:In China, the incidence of fracture non-unions is relatively high. Impaired endochondral ossification may lead to nonunion due to improper mechanical loading. As a mechanosensitive ion channel protein, Piezo1mediates mechanical transduction and induces calcium inward flow. Our early study showed that the osteogenic and angiogenic capacity of chondrocytes was reduced, if Piezo1 gene was knocked out on chondrocytes. Moreover, the expression of mitochondrion translation related gene LARS2 was signaling increased. Therefore, we hypothesize that the mechanical loading may cause endochondral ossification through the Piezo1- LARS2 signaling pathway. We will use conditioned gene knockout mice and Peizo1 knockdown stable cell line to support the hypothesis. Our goals include investigating the changes of Piezo1 expression during endochondral ossification of femoral fracture healing in mice under mechanical loading; investigating the response of Piezo1 channels on chondrocytes to mechanical stimulation and its role and mechanism in regulating chondrocyte osteogenesis and angiogenesis, maintaining the normal mitochondrial function in vitro; analysing the key molecular and signal network downstream of Piezo1 through the multi-omics techniques; and exploring the response mechanism of Piezo1 under vibrating stimulus. This project aims to study the molecular mechanism of Piezo1-mediated force-biological information transition and its role in endochondral ossification. We hope it provides an effective intervention target for preventing and treating fracture nonunion.

2024-12-19 | GSE242712 | GEO

Role of Piezo1-mediated mechanotransduction in osteocyte differentiation

Project description:Mechanical force is a fundamental regulator of bone development and homeostasis. Mechanosensitive osteocytes are the most abundant bone cells that form interconnected dendrites to respond to mechanical stimuli and interact with the bone-forming osteoblasts and the bone-remodeling osteoclasts. However, the molecular mechanisms underlying osteocyte maturation and dendrite formation remain unclear. By generating a Piezo1 "knock-out" osteocyte cell line, we identified a key role of Piezo1-mediated mechanotransduction in osteocyte differentiation. QRT-PCR analysis revealed delayed osteocyte differentiation in the Piezo1 KO cells relative to WT cells. By performing bulk RNA sequencing of WT and Piezo1 KO OCY454 cells at early (D1), intermediate (D14), and late (D28) stages of differentiation allowed for the identification of key signaling pathways in driving normal osteocyte dfiferentiation, as well as those regulated by Piezo1 mechanotransduction.

2024-09-20 | GSE277264 | GEO

E-cadherin mechanotransduction activates EGFR/ERK signaling by inducing ligand shedding

Project description:The behavior of cells is governed by signals originating from their local environment, including mechanical forces that cells experience. Forces are transduced by mechanosensitive proteins, which can impinge on signaling cascades that are also activated by growth factor receptors upon ligand binding. However, the interplay between these mechanical and biochemical signals in the regulation of intracellular signaling networks remains incompletely understood. To elucidate this mechanochemical crosstalk, we conducted phosphoproteomic and transcriptomic analyses on epithelial cells subjected to mechanical strain. This approach revealed ERK signaling as a predominant hub activated in response to intercellular forces, initiated at the level of the upstream EGF receptor. Strain-induced EGFR/ERK signaling relies on mechanosensitive E-cadherin adhesions, as it is disrupted upon genetic modulation of force transduction by the E-cadherin complex. Proximity labeling identified a connection between E-cadherin and ADAM17, an enzyme that mediates the shedding of soluble EGFR ligands. We developed a novel ADAM probe that showed that mechanical strain induces ADAM17 activity, which is essential for relaying forces to EGFR/ERK signaling. Collectively, our data demonstrate how forces transduced by E-cadherin adhesion modulate the presence of EGFR ligands to regulate downstream ERK activity. Our findings illustrate how intercellular forces and biochemical ligands can operate within a single, linear signaling cascade.

2025-11-18 | PXD052926 | Pride

Piezo1 integration of vascular architecture with physiological force LC-MSMS

Project description:The mechanisms by which physical forces regulate cells to determine complexities of vascular structure and function are enigmatic. Here we show the role the ion channel subunit Piezo1 (FAM38A). Disruption of mouse Piezo1 gene disturbed vascular development and was embryonic lethal within days of the heart beating to cause blood flow. Importance of Piezo channels as sensors of blood flow was indicated by Piezo1 dependence of shear stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer shear stress sensitivity on cells that otherwise lacked. Downstream of this calcium influx was proteoase activity and spatial organization of endothelial cells to the polarity of the applied force. Without Piezo1, normal endothelial cell organization was lacking. The data suggest Piezo1 channels as pivotal integrators of vascular architacture with physiological mechanical force.

2014-08-08 | PXD001099 | Pride

Analyze the transcriptional signature of human primary culture of CD133+ CD24+ renal progenitor cells

Project description:Podocytes and podocyte progenitors are interdependent components of the kidney's glomerular structure, with podocytes forming the glomerular filtration barrier and progenitors being key players in podocyte regeneration during pathophysiological processes. Both cell types are subjected to constant mechanical forces, whose alterations can initiate podocytopathy and worsen glomerular injury. Despite this, the specific mechanosensors and mechanotransduction pathways involved in their response to mechanical cues remain only partially explored. The role of Piezo1 silencing is studied in this dataset. In this dataset we analyzed 3 primary cell culture treated with LNA scramble or LNA Piezo1 Gapmer.

2025-09-17 | GSE273762 | GEO

E-cadherin mechanotransduction activates EGFR-ERK signaling in epithelial monolayers by inducing ADAM-mediated ligand shedding

Project description:The behavior of cells is governed by signals originating from their local environment, including mechanical forces that cells experience. Forces are transduced by mechanosensitive proteins, which can impinge on signaling cascades that are also activated by growth factor receptors upon ligand binding. However, the interplay between these mechanical and biochemical signals in the regulation of intracellular signaling networks remains incompletely understood. To elucidate this mechanochemical crosstalk, we conducted phosphoproteomic and transcriptomic analyses on epithelial monolayers subjected to mechanical strain. This approach revealed ERK signaling as a predominant strain-activated hub, initiated at the level of the upstream EGF receptor. Strain-induced EGFR/ERK signaling relies on mechanosensitive E-cadherin adhesions, as this signaling is disrupted upon genetic modulation of force transduction by the E-cadherin complex. Proximity labeling identified a connection between E-cadherin and ADAM17, an enzyme that mediates the shedding of soluble EGFR ligands. We developed a novel ADAM activity probe to demonstrate that mechanical strain induces ADAM activation, which relays mechanosensitive signaling from E-cadherin adhesions towards EGFR/ERK. Collectively, our data demonstrate how mechanical strain transduced by E-cadherin adhesion modulates the presence of EGFR ligands to regulate downstream ERK activity. Our findings illustrate how mechanical signals and biochemical ligands can operate within a single, linear signaling cascade.

2025-05-21 | GSE290599 | GEO

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