Integrin mechanosensing and cell metabolism

CD98hc links cell metabolism to integrin rigidity sensing and tissue homeostasis (2013–2019).

Between 2013 and 2019, we studied how the amino acid transporter and integrin coreceptor CD98hc (SLC3A2) links cell metabolism to integrin-mediated mechanotransduction.

In skin, CD98hc is required for normal epidermal homeostasis and wound healing, and its expression declines with age (Boulter et al., 2013). In dermal fibroblasts specifically, loss of CD98hc leads to premature-aging-like defects in the extracellular matrix and epidermal homeostasis (Tissot et al., 2018). In the context of cancer, genetic loss of CD98hc protects against Ras-driven skin tumorigenesis by modulating integrin-mediated mechanotransduction (Estrach et al., 2014), and CD98hc also contributes to tumor-stroma mechanics by helping coordinate amino acid availability that sustains tumor growth (Bertero et al., 2019).

Mechanistically, we found that CD98hc regulates integrin rigidity sensing not directly, but indirectly, through its control of sphingolipid biosynthesis, which in turn affects RhoA activation downstream of integrins (Boulter* et al., 2018). This body of work is summarized in a review on skin as a mechanical interface (Tissot et al., 2016).

References

2019

Cell Metab
Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy

Thomas Bertero, William M Oldham, Eloise M Grasset, and 12 more authors

Cell Metabolism, Jan 2019

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Dysregulation of extracellular matrix (ECM) deposition and cellular metabolism promotes tumor aggressiveness by sustaining the activity of key growth, invasion, and survival pathways. Yet mechanisms by which biophysical properties of ECM relate to metabolic processes and tumor progression remain undefined. In both cancer cells and carcinoma-associated fibroblasts (CAFs), we found that ECM stiffening mechanoactivates glycolysis and glutamine metabolism and thus coordinates non-essential amino acid flux within the tumor niche. Specifically, we demonstrate a metabolic crosstalk between CAF and cancer cells in which CAF-derived aspartate sustains cancer cell proliferation, while cancer cell-derived glutamate balances the redox state of CAFs to promote ECM remodeling. Collectively, our findings link mechanical stimuli to dysregulated tumor metabolism and thereby highlight a new metabolic network within tumors in which diverse fuel sources are used to promote growth and aggressiveness. Furthermore, this study identifies potential metabolic drug targets for therapeutic development in cancer.
@article{bertero2019tumor, title = {Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy}, author = {Bertero, Thomas and Oldham, William M and Grasset, Eloise M and Bourget, Isabelle and Boulter, Etienne and Pisano, Sabrina and Hofman, Paul and Bellvert, Floriant and Meneguzzi, Guerrino and Bulavin, Dmitry V and Estrach, Soline and Féral, Chloé C and Chan, Stephen Y and Bozec, Alexandre and Gaggioli, Cedric}, journal = {Cell Metabolism}, volume = {29}, number = {1}, pages = {124–140.e10}, year = {2019}, month = jan, doi = {10.1016/j.cmet.2018.09.012}, publisher = {Elsevier BV}, }

2018

J Invest Dermatol
Dermal Fibroblast SLC3A2 Deficiency Leads to Premature Aging and Loss of Epithelial Homeostasis

Floriane S Tissot, Soline Estrach, Etienne Boulter, and 7 more authors

Journal of Investigative Dermatology, Dec 2018

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Skin homeostasis relies on fine-tuning of epidermis-dermis interactions and is affected by aging. While extracellular matrix (ECM) proteins, such as integrins, are involved in aging, the molecular basis of the skin changes needs to be investigated further. Here, we showed that integrin co-receptor, SLC3A2, required for cell proliferation, is expressed at the surface of resting dermal fibroblasts in young patients and is reduced drastically with aging. In vivo SLC3A2 dermal fibroblast deletion induced major skin phenotypes resembling premature aging. Knockout mice (3 months old) presented strong defects in skin elasticity due to altered ECM assembly, which impairs epidermal homeostasis. SLC3A2 dermal fibroblast loss led to an age-associated secretome profile, with 77% of identified proteins belonging to ECM and ECM-associated proteins. ECM not only contributes to skin mechanical properties, but it is also a reservoir of growth factors and bioactive molecules. We demonstrate that dermal fibroblast SLC3A2 is required for ECM to fully exert its structural and reservoir role allowing proper and efficient TGF-β localization and activation. We identified SLC3A2 as a protective controller of dermal ECM stiffness and quality required to maintain the epidermis to dermis interface as functional and dynamic.
@article{tissot2018dermal, title = {Dermal Fibroblast SLC3A2 Deficiency Leads to Premature Aging and Loss of Epithelial Homeostasis}, author = {Tissot, Floriane S and Estrach, Soline and Boulter, Etienne and Cailleteau, Laurence and Tosello, Lionel and Seguin, Laetitia and Pisano, Sabrina and Audebert, Stéphane and Croce, Olivier and Féral, Chloé C}, journal = {Journal of Investigative Dermatology}, volume = {138}, number = {12}, pages = {2511–2521}, year = {2018}, month = dec, doi = {10.1016/j.jid.2018.05.026}, publisher = {Elsevier BV}, }
Nat Commun
Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway

Etienne Boulter^*, Soline Estrach^*, Floriane S Tissot, and 7 more authors

Nature Communications, Nov 2018

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Mechanical and metabolic cues independently contribute to the regulation of cell and tissue homeostasis. However, how they cross-regulate each other during this process remains largely unknown. Here, we show that cellular metabolism can regulate integrin rigidity-sensing via the sphingolipid metabolic pathway controlled by the amino acid transporter and integrin coreceptor CD98hc (SLC3A2). Genetic invalidation of CD98hc in dermal cells and tissue impairs rigidity sensing and mechanical signaling downstream of integrins, including RhoA activation, resulting in aberrant tissue mechanical homeostasis. Unexpectedly, we found that this regulation does not occur directly through regulation of integrins by CD98hc but indirectly, via the regulation of sphingolipid synthesis and the delta-4-desaturase DES2. Loss of CD98hc decreases sphingolipid availability preventing proper membrane recruitment, shuttling and activation of upstream regulators of RhoA including Src kinases and GEF-H1. Altogether, our results unravel a novel cross-talk regulation between integrin mechanosensing and cellular metabolism which may constitute an important new regulatory framework contributing to mechanical homeostasis.
@article{boulter2018cell, title = {Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway}, author = {Boulter, Etienne and Estrach, Soline and Tissot, Floriane S and Hennrich, Marco L and Tosello, Lionel and Cailleteau, Laurence and de la Ballina, Laura R and Pisano, Sabrina and Gavin, Anne-Claude and Féral, Chloé C}, journal = {Nature Communications}, volume = {9}, number = {1}, pages = {4862}, year = {2018}, month = nov, doi = {10.1038/s41467-018-07268-w}, publisher = {Springer Science and Business Media LLC}, }

2016

Eur J Cell Biol
The body’s tailored suit: Skin as a mechanical interface

Floriane S Tissot, Etienne Boulter, Soline Estrach, and 1 more author

European Journal of Cell Biology, Nov 2016

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Skin, by nature, is very similar to the Rouquayrol-Denayrouze suit mentioned by Jules Verne in Twenty Thousand Leagues Under the Sea: it allows "to risk (…) new physiological conditions without suffering any organic disorder". Mechanical cues, to the same extent as other environmental parameters, are such "new physiological conditions". Indeed, skin’s primary function is to form a protective barrier to shield inner tissues from the external environment. This requires unique mechanical properties as well as the ability to sense mechanical cues from the environment in order to prevent or repair mechanical damages as well as to function as the primary mechanosensory interface of the whole body.
@article{tissot2016body, title = {The body’s tailored suit: Skin as a mechanical interface}, author = {Tissot, Floriane S and Boulter, Etienne and Estrach, Soline and Féral, Chloé C}, journal = {European Journal of Cell Biology}, volume = {95}, number = {11}, pages = {475–482}, year = {2016}, month = nov, doi = {10.1016/j.ejcb.2016.07.001}, publisher = {Elsevier BV}, }

2014

Cancer Res
CD98hc (SLC3A2) Loss Protects Against Ras-Driven Tumorigenesis by Modulating Integrin-Mediated Mechanotransduction

Soline Estrach, Sin-Ae Lee, Etienne Boulter, and 7 more authors

Cancer Research, Nov 2014

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CD98hc (SLC3A2) is the heavy chain component of the dimeric transmembrane glycoprotein CD98, which comprises the large neutral amino acid transporter LAT1 (SLC7A5) in cells. Overexpression of CD98hc occurs widely in cancer cells and is associated with poor prognosis clinically, but its exact contributions to tumorigenesis are uncertain. In this study, we showed that genetic deficiency of CD98hc protects against Ras-driven skin carcinogenesis. Deleting CD98hc after tumor induction was also sufficient to cause regression of existing tumors. Investigations into the basis for these effects defined two new functions of CD98hc that contribute to epithelial cancer beyond an intrinsic effect of CD98hc on tumor cell proliferation. First, CD98hc increased the stiffness of the tumor microenvironment. Second, CD98hc amplified the capacity of cells to respond to matrix rigidity, an essential factor in tumor development. Mechanistically, CD98hc mediated this stiffness sensing by increasing Rho kinase (ROCK) activity, resulting in increased transcription mediated by YAP/TAZ, a nuclear relay for mechanical signals. Our results suggest that CD98hc contributes to carcinogenesis by amplifying a positive feedback loop, which increases both extracellular matrix stiffness and resulting cellular responses. This work supports a rationale to explore the use of CD98hc inhibitors as cancer therapeutics.
@article{estrach2014cd98hc, title = {CD98hc (SLC3A2) Loss Protects Against Ras-Driven Tumorigenesis by Modulating Integrin-Mediated Mechanotransduction}, author = {Estrach, Soline and Lee, Sin-Ae and Boulter, Etienne and Pisano, Sabrina and Errante, Aurélia and Tissot, Floriane S and Cailleteau, Laurence and Pons, Catherine and Ginsberg, Mark H and Féral, Chloé C}, journal = {Cancer Research}, volume = {74}, number = {23}, pages = {6878–6889}, year = {2014}, month = nov, doi = {10.1158/0008-5472.can-14-0579}, publisher = {American Association for Cancer Research (AACR)}, }

2013

J Exp Med
CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

Etienne Boulter, Soline Estrach, Aurélia Errante, and 5 more authors

Journal of Experimental Medicine, Jan 2013

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Skin aging is linked to reduced epidermal proliferation and general extracellular matrix atrophy. This involves factors such as the cell adhesion receptors integrins and amino acid transporters. CD98hc (SLC3A2), a heterodimeric amino acid transporter, modulates integrin signaling in vitro. We unravel CD98hc functions in vivo in skin. We report that CD98hc invalidation has no appreciable effect on cell adhesion, clearly showing that CD98hc disruption phenocopies neither CD98hc knockdown in cultured keratinocytes nor epidermal β1 integrin loss in vivo. Instead, we show that CD98hc deletion in murine epidermis results in improper skin homeostasis and epidermal wound healing. These defects resemble aged skin alterations and correlate with reduction of CD98hc expression observed in elderly mice. We also demonstrate that CD98hc absence in vivo induces defects as early as integrin-dependent Src activation. We decipher the molecular mechanisms involved in vivo by revealing a crucial role of the CD98hc/integrins/Rho guanine nucleotide exchange factor (GEF) leukemia-associated RhoGEF (LARG)/RhoA pathway in skin homeostasis. Finally, we demonstrate that the deregulation of RhoA activation in the absence of CD98hc is also a result of impaired CD98hc-dependent amino acid transports.
@article{boulter2013cd98hc, title = {CD98hc (SLC3A2) regulation of skin homeostasis wanes with age}, author = {Boulter, Etienne and Estrach, Soline and Errante, Aurélia and Pons, Catherine and Cailleteau, Laurence and Tissot, Floriane and Meneguzzi, Guerrino and Féral, Chloé C}, journal = {Journal of Experimental Medicine}, volume = {210}, number = {1}, pages = {173–190}, year = {2013}, month = jan, doi = {10.1084/jem.20121651}, publisher = {Rockefeller University Press}, }