Trends in Biochemical Sciences
OpinionPI3K functions as a hub in mechanotransduction
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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Regulation of protein synthesis and stability by mechanical cues and its implications in cancer
2024, Current Opinion in Cell BiologyThe role of RAS oncogenes in controlling epithelial mechanics
2023, Trends in Cell BiologyCitation 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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