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Peristalsis-Associated Mechanotransduction Drives Malignant Progression of Colorectal Cancer

  • SI: 2023 CMBE Young Innovators
  • Published:
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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.

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Data Availability

Data supporting the findings of this study are deposited into a Texas Data Repository with the following https://doi.org/10.18738/T8/TJTOZN.

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Acknowledgements

This work was supported by the Cancer Prevention and Research Institute of Texas CPRIT RP230204 “Gene-environment-lifestyle interactions in cancer” (SR), and NIH R37CA269224-01A1 (SR). This work was additionally supported by the Texas A&M Engineering Experiment Station and the Department of Biomedical Engineering at Texas A&M University. The authors acknowledge the assistance of Dr. Malea Murphy at the Integrated Microscopy and Imaging Laboratory at Texas A&M School of Medicine, RRID:SCR_021637. The authors also acknowledge the support from Steven Foncerrada and Sufiyan Sabir for assistance with protein quantification experiments. The authors acknowledge support from the Kopetz lab at MD Anderson, and Dr. Preeti Kanikarla for generating the PDX lines used in this study.

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  1. Department of Biomedical Engineering, Texas A&M University, 5016 Emerging Technologies Building, 3120 TAMU, College Station, TX, 77843, USA

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

  2. Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Amber N. Stratman

  3. Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA

    Shreya A. Raghavan

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Abigail Clevenger, Maygan McFarlin, Claudia Collier, Vibha Sheshadri, Anirudh Madyastha, John Paul Gorley, Spencer Solberg, Amber Stratman, and Shreya Raghavan declare that they have no conflicts of interest.

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Clevenger, A.J., McFarlin, M.K., Collier, C.A. et al. Peristalsis-Associated Mechanotransduction Drives Malignant Progression of Colorectal Cancer. Cel. Mol. Bioeng. 16, 261–281 (2023). https://doi.org/10.1007/s12195-023-00776-w

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