Mechanical Stretch Kills Transformed Cancer Cells

Ajay Tijore, Mingxi Yao, Yu-Hsiu Wang, Yasaman Nematbakhsh, Anushya Hariharan, Chwee Teck Lim, Michael Sheetz

Preprint posted on 10 December 2018

Use the force: Mechanoptosis specifically kills transformed cancer cells

Selected by Joseph Jose Thottacherry

Background: Mechanics plays an important role in regulating cell migration, growth, development and apoptosis. Such mechanically induced apoptosis is termed mechanoptosis. Substrate rigidity and attachment is important for growth of normal cells, in the absence of which they undergo programmed cell death called anoikis. Transformed cancer cells are resistant to anoikis and therefore proliferation of cells in soft agar is used as a classical test to identify them. These transformed cancer cells cannot sense matrix rigidity and a previous preprint from the same group showed the importance of cytoskeletal components (especially TPM2.1) in cancer cell survival (Yang et al. 2018). However, many other reports point to how forces could impede cancer growth, even in mice (Berrueta et al. 2018, Lien et al. 2013, Regmi et al. 2017). In this preprint, the authors test the importance of forces in selective apoptosis of cancer cells and the mechanisms regulating these.

Key findings of the preprint: Although cancer cells are resistant to anoikis, the authors find that they are extremely sensitive to mechanoptosis. Upon cyclic stretch, transformed cancer cells show reduced growth and become apoptotic. This can be rescued by addition of TPM2.1 protein that also helps in sensing matrix rigidity. On the other hand, cyclic stretching of normal cells results in increased cell growth even on soft agar, thereby rescuing these cells from anoikis. While anoikis of normal cells or cancer cells restored with TPM2.1 depend on death associated protein kinase 1, mechanoptosis involves a different molecular mechanism. The authors find that mechanosensitive calcium channel Piezo1-mediated calcium influx and accumulation is important for mechanoptosis of cancer cells. In response to accumulated calcium, calcium dependent calpain 2 protein is activated, which triggers the downstream BAX-mediated mitochondrial apoptotic pathway. In normal cells, the calcium concentration is tightly maintained and it mediates cell proliferation possibly by a YAP-mediated mechanism (Aragona et al. 2013, Cui et al. 2015).

Image adapted from Tijore et al., 2018 with permission from authors.


What I liked about this preprint: This is a very interesting study that delineates substrate rigidity from strain experienced by a cell. Although TPM2.1 levels are essential for both of the responses, the downstream pathways are very different. The authors have used multiple cancer lines and can rescue these effects as well. Further, normal cells can be transformed and show similar phenotypes, which shows that this is not an indirect global effect. This work shows the importance of mechanics in regulating cellular phenotypes and dissects the specific molecular mechanisms giving rise to these cellular fates.

Future directions and questions for the authors: It would be very interesting to test the importance of mechanics in tumor apoptosis in an in vivo context and see if these principles still apply. It would also be very interesting to test the role of mechanics in cancer organoid cultures. To authors: The paper starts with the difference in substrate rigidity in determining the response (here, aspect ratio or AR) of cancer cells and how this can be rescued by addition of TPM 2.1. So how is AR connected to growth defect or apoptosis? How does TPM2.1 level regulate Piezo activity?


Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, et al. 2013. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell. 154(5):1047–59
Berrueta L, Bergholz J, Munoz D, Muskaj I, Badger GJ, et al. 2018. Stretching Reduces Tumor Growth in a Mouse Breast Cancer Model. Sci. Rep. 8(1):1–7
Cui Y, Hameed FM, Yang B, Lee K, Pan CQ, et al. 2015. Cyclic stretching of soft substrates induces spreading and growth. Nat. Commun. 6:1–8
Lien SC, Chang SF, Lee PL, Wei SY, Chang MDT, et al. 2013. Mechanical regulation of cancer cell apoptosis and autophagy: Roles of bone morphogenetic protein receptor, Smad1/5, and p38 MAPK. Biochim. Biophys. Acta – Mol. Cell Res. 1833(12):3124–33
Regmi S, Fu A, Luo KQ. 2017. High Shear Stresses under Exercise Condition Destroy Circulating Tumor Cells in a Microfluidic System. Sci. Rep. 7(August 2016):1–12
Yang B, Wolfenson H, Nakazawa N, Liu S, Hu J, Sheetz M. 2018. Stopping Transformed Growth with Cytoskeletal Proteins: Turning a Devil into an Angel. bioRxiv. 221176

Tags: cancer, mechanobiology

Posted on: 3 February 2019


Read preprint (1 votes)

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the cell biology category:


The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!


List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.


List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020


List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.


List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria


List by Dey Lab, Samantha Seah


Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.


List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20


List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.


List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome


List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)


List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019


List by Dey Lab


Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.


List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.


List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.


List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019


List by Dey Lab


This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.


List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA


List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.


List by Dey Lab, Amanda Haage