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Calpain-2 regulates hypoxia/HIF-induced amoeboid reprogramming and metastasis

Veronika te Boekhorst, Liying Jiang, Marius Mählen, Maaike Meerlo, Gina Dunkel, Franziska C. Durst, Yanjun Yang, Herbert Levine, Boudewijn M. T. Burgering, Peter Friedl

Posted on: 29 January 2020

Preprint posted on 6 January 2020

Calpain-2 activity on Talin is required for hypoxia induced conversion to an ameboid/blebbing migration mode in cancer cells

Selected by Amanda Haage

Why This Is Cool – Cancer metastasis is a particularly deadly disease progression due not only to its systemic spread, but also its plasticity. Essentially every therapeutic strategy aimed at stopping cancer cell migration has failed because these cells use many different modes of migration across a diverse set of contexts. Much work has gone into defining these modes and even relating them to specific contexts, but the authors go a step further here and provide a convincing mechanism behind how cancer cells can achieve shifts in migration mode.

They start in vitro using both mouse and human cell lines, commonly used as models for metastasis, to better characterize hypoxia induced amoeboid migration. A range of protrusions are identified in cells individually migrating away from a tumor spheroid in response to hypoxia, stabilizing towards blebbing over time. These cells have reduced integrin activation and ectopic activation induced less round morphology. The authors then hypothesize that this ameboid/low adhesive migration mode may be due to calpain-2 activity for two reasons 1) calpain-2  is known to be upregulated in metastasis1 and 2) it is known to cleave adaptor proteins2 facilitating focal adhesion turnover. Several pieces of evidence are then presented to confirm this hypothesis, including in specific relation to the points above that 1) calpain-2 expression and activity increased under hypoxia and 2) Talin-1 (a focal adhesion adaptor) cleavage at the calpain-2 site was necessary for induced ameboid migration. The strongest piece of evidence unsurprisingly comes from in vivo data demonstrating a decrease in hypoxia induced lung metastases with drug treatment to inhibit calpain activity.

 

Why I Selected It – The Friedl lab has a long-standing history in defining the different modes of migration3 used by cancer cells. Their work is some of the foundational studies to my career in microenvironmental regulation of cell migration. As far as I know, this is the first time Talin has entered this conversation, the protein I spent my post-doctoral work on4, and I think it’s a very interesting juxtaposition. We know Talin as the master of integrin adhesions5 and we know that these different modes of migration have different adhesion requirements6. I don’t think it’s surprising that Talin would therefore also have a hand in mastering the modes of migration used by cells in various contexts.

 

Open Questions –

  1. Why would calpain-2 be a better therapeutic target than Talin itself?
  2. With pharmacological inhibition of calpain-2, what’s stopping cancer cells taking up a more mesenchymal mode of migration and still producing metastasis?
  3. Or is this possibly an epithelial cancer specific therapeutic possibility due to it’s strong link with hypoxia?

 

Related References –

1. Calpain activity and expression is upregulated in metastasis

Zhang, S. et al. Calpain system protein expression and activity in ovarian cancer. J. Cancer Res. Clin. Oncol. 145, 345–361 (2019).

2. Calpain’s cleave various adhesion regulating proteins, including Talin

Franco, S. J. & Huttenlocher, A. Regulating cell migration: calpains make the cut. J. Cell Sci. 118, 3829–3838 (2005).

3. Reviewing the Friedl lab’s work on cell migraiton modes

Friedl, P. & Wolf, K. Plasticity of cell migration: a multiscale tuning model. J. Cell Biol. 188, 11–19 (2010).

4. One of my recent works in the Talin field

Haage, A. et al. Talin Autoinhibition Regulates Cell-ECM Adhesion Dynamics and Wound Healing In Vivo. Cell Rep. 25, 2401-2416.e5 (2018).

5. Talin regulates all things integrin

Klapholz, B. & Brown, N. H. Talin – the master of integrin adhesions. J. Cell Sci. 130, 2435–2446 (2017).

6. Various migration modes have specific cell to extracellular matrix adhesion requirements

Zhu, J. & Mogilner, A. Comparison of cell migration mechanical strategies in three-dimensional matrices: a computational study. Interface Focus 6, (2016).

 

doi: https://doi.org/10.1242/prelights.16584

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