RIGIDITY SENSING

Life and death agendas of actin filaments

Cancer cells have now been shown to lack rigidity-sensing due to alteration in cytoskeletal sensor proteins, but can be reversed from a transformed to a rigidity-dependent growth state by the sensor proteins, resulting in restoration of contractility and adhesion.

The mechanism of rigidity-sensing by actin filaments is fundamental to the survival of normal cells and the elimination of rogue cells that disengage from their physical environment. The rigidity sensing mechanism detects a change to a mechanically ‘softer’ environment and triggers cell death via anoikis. However, this mechanism is altered by cancer cells to subvert their sensitivity to changes in their interaction with their material environment and ensure their survival. Writing in Nature Materials, Michael Sheetz and colleagues have now built on their previous work on identification of cell contractile units (CUs), which tests the rigidity of their environment, to show that CUs are independent of cell lineage and are dependent on two key components1: actin filaments containing the tropomyosin Tpm2.1 and their engagement with the conventional myosin motor, MyoIIA. Cell transformation requires the elimination of this sensing mechanism. When present, this sensing mechanism acts to prevent cancer by driving cells that disengage from their material environment into apoptosis via anoikis. Sheetz and colleagues demonstrate that incapacitation of this sensing mechanism can be achieved by down regulation of either Tpm2.1 or MyoIIA or by replacement of Tpm2.1 by the cancer associated isoform, Tpm3.1. Most importantly, the authors provide a molecular explanation of how the change in the physical interaction of CUs with the extracellular matrix determines the transformed state of the cell in terms of cell proliferation.

Previous studies by the Sheetz laboratory have demonstrated that Tpm2.1-containing actin filaments can exert mechanical force on the material environment using displacement of pillars in a stepwise manner as a measure of this mechanical force2. The nature of this cellular pulling force is consistent with the progressive engagement of a MyoII motor to generate stepwise contraction that can be detected by movement of pillars underlying the cell (Fig. 1). The composition of this rigidity-sensing complex appears to involve the focal adhesion machinery, growth factor receptors and the death-associated protein kinase 1 (DAPK-1) linked through contractile actin filaments containing Tpm2.1 and MyoIIA. Under conditions where the cell interacts with soft material surfaces, the ability of this complex to generate tension is compromised and cell death is initiated, probably through activation of DAPK-13. Thus, the rigidity sensor integrates sensing of a soft environment with initiation of anoikis (the cell death pathway regulated by this sensing mechanism).

Fig. 1: Actin filaments with opposing life and death agendas.
figure1

Normal cells build a rigidity-sensor complex composed of co-polymers of actin and the tropomyosin Tpm2.1 (green), myosin IIA motors, growth factor receptors (GFR) and death-associated protein kinase-1 (DAPK-1). When the rigidity sensor identifies a hard or stiff substrate, the cell can survive but sensing of a soft substrate can trigger a death response most likely to be via activation of DAPK-1. However, displacement of Tpm2.1 by the cancer-associated isoform Tpm3.1 (pink) still allows the actin filaments to engage MyoIIA, but the resulting complex no longer functions as a rigidity sensor and cell growth becomes impervious to the compliance of the material surface. Downregulation of either Tpm2.1 or MyoIIA is also sufficient to nullify the function of the rigidity sensor, resulting in cell survival on a soft substrate.

Sheetz and colleagues demonstrate that down regulation of Tpm2.1 or MyoIIA are each capable of shifting cells from rigidity-sensitive to a rigidity-insensitive growth independent of the cell lineage. This is a highly penetrant phenotype first observed in viral transformation almost 40 years ago and is indicative of a fundamental cell survival mechanism that aligns with the observation that down regulation of Tpm2.1 is an early indicator of transformation in many cell lineages4,5 (Fig. 1). The challenge has been to understand what makes Tpm2.1 so specific for this mechanism. Mammalian cells have the potential to make many tropomyosin isoforms that form co-polymers with actin. The tropomyosin present in an actin filament determines the functional capacity of that filament in an isoform-specific manner6. It is therefore expected that the functional properties of Tpm2.1-containing actin filaments are unique to that isoform and it has recently been demonstrated that tropomyosins determine the outcome of engagement with a MyoII motor in an isoform-specific manner7. Similarly, Sao et al.8 have shown that interaction of MyoII motors with Tpm2.1- and Tpm1.6-containing actin filaments in the same cell independently regulate different mechanisms of cell migration. The specific features of MyoIIA engagement with a Tpm2.1 actin filament required for this rigidity sensor are currently unknown.

The issue of actin/Tpm filament specificity in this rigidity sensor has now been clarified by Sheetz and colleagues During the development of cancer there is an increasing shift in the tropomyosin repertoire toward primary reliance on the isoform Tpm3.14,9. The authors report that elevated expression of Tpm3.1 in the absence of changes in the levels of Tpm2.1 and MyoIIA is sufficient to abolish the function of the rigidity sensor. They further find that increased Tpm3.1 can displace Tpm2.1 from the cell periphery and that Tpm3.1-containing actin filaments do not recapitulate the function of the rigidity sensor. This focuses attention on the difference between engagement of Tpm2.1- and Tpm3.1-containing actin filaments with MyoIIA. It is well established that Tpm2.12 and Tpm3.110 actin filaments engage with MyoIIA. The mechanistic discrimination between these tropomyosins may reflect differences in the mechanical readout that changes when Tpm3.1 replaces Tpm2.1 in the ‘same’ actin filament7 or is it a change in the engagement of the tropomyosin isoform with other components of the CU complex.

The final piece of the puzzle is the recent finding that of the four tropomyosin isoforms tested including Tpm2.1, only one, Tpm3.1, inhibits apoptosis induced by nine different inducers11. This suggests that the reliance of cancer cells on Tpm3.1 may not only relate to the positive functions of this isoform in cell proliferation and glucose uptake, but may also be related to its ability to promote cell survival under conditions that would normally cause cell death including its ability to override anoikis. It remains to be established if this Tpm3.1-mediated resistance to apoptosis operates in tumours. Overall, these findings illustrate the importance of the balance between Tpm2.1- and Tpm3.1-containing actin/Tpm filaments in deciding the survival of cancer cells.

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Correspondence to Edna C. Hardeman.

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E.C.H. and P.W.G. are directors and shareholders in TroBio Therapeutics Pty Ltd, a company commercializing the use of anti-tropomyosin drugs.

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Hardeman, E.C., Gunning, P.W. Life and death agendas of actin filaments. Nat. Mater. 19, 135–136 (2020). https://doi.org/10.1038/s41563-019-0583-1

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