Mechanical Stretch Kills Transformed Cancer Cells
Preprint posted on December 10, 2018 https://www.biorxiv.org/content/10.1101/491746v2
A hallmark of transformed cancer cells is their ability to grow on soft substrate, which is often correlated with their loss of matrix rigidity-sensing ability 1. Previous studies demonstrated that alteration in expression of cytoskeleton proteins in transformed cancer cells could restore rigidity sensing and help in blocking growth 2,3. Recent studies have provided some evidence in support of mechanical force-dependent growth inhibition in a mice model; gentle stretching of mice (10 minutes of stretching/day for 4-weeks) resulted in inhibition of tumor growth 4,5. Authors of this preprint report a very intriguing finding that transformed cancer cells from various tissue origins, when subjected to cyclic mechanical stretching, inhibit their growth and undergo apoptosis.
The authors show that 6 hours of cyclic stretching of rigidity-dependent transformed cancer cells, which lack expression of cytoskeletal protein TPM2.1 (key protein in rigidity sensing 6), results in cell elongation. Exogenous expression of TPM2.1 could restore rigidity sensing, and inhibited cyclic-stretching-dependent cell elongation. Further, the authors report that cyclic stretching inhibited the growth of transformed cells, while facilitating normal cell growth. This was attributed to increased apoptosis in transformed cells and reduced apoptosis in normal cells upon cyclic stretching.
The authors perform elegant experiments to elucidate a mechanistic pathway of this process: cyclic stretching results in increases in the influx of calcium, which activates calpain protease. This further acts on Bax to induce the mitochondrial apoptotic pathway, eventually leading to cell death.
Importance and Future questions
This study reveals that mechanical sensitivity of tumor cells is related to transformed cell state and not linked to tissue origin or cell type. This raises the possibility to exploit this process in animal models to specifically damage tumor cells and simultaneously promote normal cell growth. These findings will help in understanding and designing a better set up to utilize mechanical force based therapy.
It would be interesting to see when the growth of “normal cells” post cyclic stretching comes down to the non-stretched state. Do the normal cells in a mixture of transformed cancer cells have a mechanoprotective role?
- Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
- Yang, B. et al. Stopping Transformed Growth with Cytoskeletal Proteins: Turning a Devil into an Angel. bioRxiv 221176 (2018). doi:10.1101/221176
- Wolfenson, H. et al. Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices. Nat. Cell Biol. 18, 33–42 (2016).
- Berrueta, L. et al. Stretching Reduces Tumor Growth in a Mouse Breast Cancer Model. Sci. Rep. 8, 7864 (2018).
- Betof, A. S. et al. Modulation of Murine Breast Tumor Vascularity, Hypoxia, and Chemotherapeutic Response by Exercise. JNCI J. Natl. Cancer Inst. 107, (2015).
- Stehn, J. R. et al. A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells. Cancer Res. 73, 5169–5182 (2013).
Posted on: 5th February 2019Read preprint
Also in the cell biology category:
The autophagic membrane tether ATG2A transfers lipids between membranes
|Selected by||Sandra Malmgren Hill|
LTK is an ER-resident receptor tyrosine kinase that regulates secretion
|Selected by||Nicola Stevenson|
Distinct RhoGEFs activate apical and junctional actomyosin contractility under control of G proteins during epithelial morphogenesis
|Selected by||Ivana Viktorinová|
In vivo glucose imaging in multiple model organisms with an engineered single-wavelength sensor
|Selected by||Stephan Daetwyler|
The spindle assembly checkpoint functions during early development in non-chordate embryos
|Selected by||Maiko Kitaoka|
Blue light induces neuronal-activity-regulated gene expression in the absence of optogenetic proteins
|Selected by||Zheng-Shan Chong|
Mutations in the Insulator Protein Suppressor of Hairy Wing Induce Genome Instability
|Selected by||Maiko Kitaoka|
Multi-immersion open-top light-sheet microscope for high-throughput imaging of cleared tissues
|Selected by||Tim Fessenden|
ATAT1-enriched vesicles promote microtubule acetylation via axonal transport
|Selected by||Stephen Royle|
HIV-1 Gag specifically restricts PI(4,5)P2 and cholesterol mobility in living cells creating a nanodomain platform for virus assembly
|Selected by||Amberley Stephens|
Hepatocyte-specific deletion of Pparα promotes NASH in the context of obesity
|Selected by||Pablo Ranea Robles|
Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases
|Selected by||Sandra Franco Iborra|
Thyroid hormone regulates distinct paths to maturation in pigment cell lineages
|Selected by||Hannah Brunsdon|
Kinesin-6 Klp9 plays motor-dependent and -independent roles in collaboration with Kinesin-5 Cut7 and the microtubule crosslinker Ase1 in fission yeast
|Selected by||I. Bouhlel|
A pair of E3 ubiquitin ligases compete to regulate filopodial dynamics and axon guidance
|Selected by||Angika Basant|
SorCS1-mediated Sorting of Neurexin in Dendrites Maintains Presynaptic Function
|Selected by||Carmen Adriaens|