Peristalsis-Associated Mechanotransduction Drives Malignant Progression of Colorectal Cancer.

IF 2.3 4区医学 Q3 BIOPHYSICS

Cellular and molecular bioengineering Pub Date : 2023-08-11 eCollection Date: 2023-08-01 DOI:10.1007/s12195-023-00776-w

Abigail J Clevenger, Maygan K McFarlin, Claudia A Collier, Vibha S Sheshadri, Anirudh K Madyastha, John Paul M Gorley, Spencer C Solberg, Amber N Stratman, Shreya A Raghavan

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引用次数: 0

Abstract

Introduction: In the colorectal cancer (CRC) tumor microenvironment, cancerous and precancerous cells continuously experience mechanical forces associated with peristalsis. Given that mechanical forces like shear stress and strain can positively impact cancer progression, we explored the hypothesis that peristalsis may also contribute to malignant progression in CRC. We defined malignant progression as enrichment of cancer stem cells and the acquisition of invasive behaviors, both vital to CRC progression.

Methods: We leveraged our peristalsis bioreactor to expose CRC cell lines (HCT116), patient-derived xenograft (PDX1,2) lines, or non-cancerous intestinal cells (HIEC-6) to forces associated with peristalsis in vitro. Cells were maintained in static control conditions or exposed to peristalsis for 24 h prior to assessment of cancer stem cell (CSC) emergence or the acquisition of invasive phenotypes.

Results: Exposure of HCT116 cells to peristalsis significantly increased the emergence of LGR5⁺ CSCs by 1.8-fold compared to static controls. Peristalsis enriched LGR5 positivity in several CRC cell lines, notably significant in KRAS mutant lines. In contrast, peristalsis failed to increase LGR5⁺ in non-cancerous intestinal cells, HIEC-6. LGR5⁺ emergence downstream of peristalsis was dependent on ROCK and Wnt activity, and not YAP1 activation. Additionally, HCT116 cells adopted invasive morphologies when exposed to peristalsis, with increased filopodia density and epithelial to mesenchymal gene expression, in a Wnt dependent manner.

Conclusions: Peristalsis associated forces drive malignant progression of CRC via ROCK, YAP1, and Wnt-related mechanotransduction.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-023-00776-w.

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外周组织相关的机制传导驱动癌症结直肠癌的恶性进展。

简介：在癌症（CRC）肿瘤微环境中，癌细胞和癌前细胞持续经历与蠕动相关的机械力。考虑到剪切应力和应变等机械力可以积极影响癌症的进展，我们探讨了蠕动也可能导致CRC恶性进展的假设。我们将恶性进展定义为癌症干细胞的富集和侵袭行为的获得，这两种行为对CRC进展都至关重要。方法：我们利用我们的蠕动生物反应器在体外将CRC细胞系（HCT116）、患者来源的异种移植物（PDX1,2）系或非癌性肠细胞（HIEC-6）暴露于与蠕动相关的力。在评估癌症干细胞（CSC）出现或获得侵袭表型之前，将细胞维持在静态对照条件下或暴露于蠕动24小时。结果：与静态对照相比，HCT116细胞暴露于蠕动显著增加了LGR5+CSC的出现1.8倍。在几种CRC细胞系中，围生期富集了LGR5阳性，在KRAS突变系中显著。相反，在非癌性肠细胞HIEC-6中，蠕动不能增加LGR5+。LGR5+在蠕动下游的出现依赖于ROCK和Wnt活性，而不是YAP1活性。此外，HCT116细胞在暴露于蠕动时采用侵袭形态，丝足密度增加，上皮-间充质基因表达增加，呈Wnt依赖性。结论：围生期相关的力通过ROCK、YAP1和Wnt相关的机械转导驱动CRC的恶性进展。补充信息：在线版本包含补充材料，网址为10.1007/s12195-023-00776-w。

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.