Opinion
PI3K functions as a hub in mechanotransduction

https://doi.org/10.1016/j.tibs.2021.05.005Get rights and content

Highlights

  • Class I and class II phosphatidylinositol 3-kinase (PI3K) activation is necessary for the rapid intracellular signal transduction of all mechanical stresses (shear, tension, compression); among those, kilopascal-range compressive stress promotes strong engagement of class I PI3Ks.

  • Class I PI3Ks are upstream activators of the YAP/TAZ pathway; mechanical stress is permissive for their control of YAP/TAZ and targeting of PI3K is a novel strategy to hinder YAP/TAZ oncogenic dependence.

  • In response to tension, integrins, cadherins, and ion channels undergo conformational changes, which initiates diverse cytosolic signals including hyperactivation of the class I PI3Ks.

  • The cytoskeleton forms a rigid network that responds to physical forces. Early signal events lead to PI3K activation to activate small GTPases controlling actin cytoskeleton remodeling.

  • Nutrient availability and metabolic state control the cell’s adaptive response to mechanics via PI3Ks; mechanics induce PI3K-dependent rewiring of cell metabolism (class I) and autophagy (class II).

Mammalian cells integrate different types of stimuli that govern their fate. These stimuli encompass biochemical as well as biomechanical cues (shear, tensile, and compressive stresses) that are usually studied separately. The phosphatidylinositol 3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. Recent evidence in cancer research demonstrates that these enzymes are essential in mechanotransduction. Despite this, the importance of the integration of biomechanical cues and PI3K-driven biochemical signals is underestimated. In this opinion article, we make the hypothesis that modeling of biomechanical cues is critical to understand PI3K oncogenicity. We also identify known/missing knowledge in terms of isoform specificity and molecular pathways of activation, knowledge that is needed for clinical applications.

Section snippets

Mechanical stresses and PI3K signaling in cancer

Mechanical stresses (see Glossary) are ubiquitous in nature. Cells can be stretched or compressed, even deformed (Box 1). Solid tumors are a setting where all types of mechanical stresses can be encountered and experienced by cancer and stromal cells. Although precise mapping of the mechanical stress sensed by tumor cells is unknown, techniques are being developed to improve in vivo measurements [1]. Additionally, recent experimental efforts have been directed towards the in vitro modeling of

Mechanosensing and downstream activation

One of the major challenges in the field remains the understanding of how a mechanical stress is transduced into a biochemical signal leading to a cellular phenotype, and numerous efforts have been made to decipher sensing mechanisms resulting from the modulation of stiffness.

The generic biophysical modifications associated with changes of stiffness are increases in membrane and cortex tension [4]. This increase has been shown to trigger, in particular, mechanosensors such as the

Mechanical cues activate class I PI3K in cancer

It is well established that reversible phosphorylation of plasma membrane inositol lipids controls diverse functions in cells and that this phosphorylation by PI3K allows a cascade of phosphorylation events downstream, including phosphorylation and activation of AKT and the subsequent activation of mTOR in the mTORC1 complex [16] (Figure 1A). This signaling pathway is involved in the activation of cell growth, proliferation, anchorage, migration, and metabolism and controls autophagy. In many

Modulation of compressive stress activates PI3K signaling to promote cell migration, proliferation, survival, and possibly drug resistance

Kalli et al. showed that compression of pancreatic cancer cells promotes a migratory phenotype via an autocrine loop involving PI3K activation [23]. The coupling of mechanical stress and PI3K/AKT pathway activation was also shown to be involved in the regulation of cell death; activation of class I PI3Ks via adhesive molecules, such as N-cadherin, protects against cell death induced by a wide range of compressive stresses [31]. It should be noted that both of these studies were performed using

Class I PI3Ks are upstream activators of the YAP/TAZ transcriptional pathway

Mechanotransduction relates to the conversion of a mechanical stimulus from the environment into a biochemical response [10], and cell adaptation to mechanical stress is so far mainly described in terms of gene expression. The transcriptional activators YAP/TAZ in the Hippo pathway are major controllers of gene expression on mechanical stress [7,9]. Three recent studies place PI3K signaling upstream of mechanically induced YAP/TAZ activation [35., 36., 37.], positioning PI3K activation as a

PI3K activation controls cell cytoskeleton remodeling on mechanical stimulation

Beyond YAP/TAZ transcriptional activation, mechanical cues also trigger cell cytoskeleton remodeling. The latter is critically controlled by focal adhesions and cell–cell adherens and tight junctions that mediate bidirectional physical communication between cells and the extracellular matrix (ECM)/neighboring cells (Figure 1B).

In focal adhesions, ECM binding to integrin or mucins (e.g., MUC13) activates PI3K activity that enhances the activation of small GTPases such as Cdc42 or RhoA [36,42,44,

Mechanical cell transduction can involve class I-, II-, and III-PI3K-dependent regulation of metabolism and autophagy

In the context of mechanically induced contraction of mammalian cells, metabolic reprogramming promotes proinvasive properties [24] (Figure 1C). PI3K coordinates glycolysis with cytoskeletal dynamics through the control of aldolase localization in an AKT-independent manner [51]. Additionally, it was shown that the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolysis rates in lung cancer cells [52]. Increased PI3K activity in tumor cells could

Novel concepts in mechanics: PI3K signal coupling

In summary, the current evidence argues for isoform-selective roles triggered by specific biomechanical cues. PI3Kα could be linked to tensile and stretching cell adaptation through modulation of the actin cytoskeleton and could control YAP/TAZ activity under nutrient-rich conditions. PI3Kβ could respond to growth-induced compression and loss of organized cell–cell adhesion, being critical for YAP/TAZ activation in those contexts. PI3Kδ could control epithelial cell loss of polarity (Figure 1

Concluding remarks

Mechanotransduction of tensile stress in cancer [59] and the importance of matrix-induced compression in drug delivery through blood vessel clamping [60] are now well accepted concepts in cancer biology. These assumptions led to the development of innovative mechanotherapeutics, currently mostly tested in pancreatic cancer but not validated in humans [61]. Given the recent literature, we are convinced that as-yet-unknown PI3K isoform-selective-induced signals may also play a pivotal role in

Acknowledgments

We apologize to the authors whose work could not be cited due to limited space. Our work on this topic is funded by Fondation Toulouse Cancer Santé (Mecharesist) and Inserm Plan Cancer (PressDiagTherapy). We thank our colleagues for their critical reading of the manuscript.

Declaration of interests

No interests are declared.

Glossary

Actin cortex
a thin, contractile layer of filamentous actin, myosin motors, and regulatory proteins beneath the plasma membrane crucial to cytokinesis, morphogenesis, and cell migration.
Autophagy
allows the orderly degradation and recycling of cellular components. Phosphatidylinositol 3-phosphate (PI-3-P) controls autophagy initiation.
Basal surface
at the basal surface, the basement membrane is a thin layer of ECM that provides cell and tissue support.
Cell–cell adherens and tight junctions
adherens

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    • The role of RAS oncogenes in controlling epithelial mechanics

      2023, Trends in Cell Biology
      Citation Excerpt :

      In the context of cancer, the expression and nuclear translocation of YAP were also shown to be altered by constitutive activation of PI3K and the downstream effector phosphoinositide-dependant kinase (PDK1) [51,52], post-transcription modifications through the RAS-MAPK pathway [53], and direct phosphorylation of TEAD3 through increased oncogenic RAS-ERK signalling [22]. Particularly, there is growing evidence supporting the mechanotransduction role of PI3K-PDK1 in regulating YAP/TAZ signalling in development [54] and oncogenesis [55]. Although these data show that oncogenic RAS modulates cell–substrate interactions and mechanosensing, most of these studies have been carried out in single or sparsely plated cells.

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