Mechanical Control of Cell Proliferation Increases Resistance to Chemotherapeutic Agents

Rizzuti, Ilaria Francesca; Mascheroni, Pietro; Arcucci, Silvia; Meriem, Zacchari Ben; Prunet, Audrey; Barentin, Catherine; Rivière, Charlotte; Delanoë-Ayari, Hélène; Hatzikirou, Haralampos; Guillermet-Guibert, Julie; Delarue, Morgan

doi:10.1103/physrevlett.125.128103

Cited by 46 publications

(41 citation statements)

References 40 publications

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“…To proliferate in confinement, cells must push on the boundaries of their environment and neighboring cells, leading to development of compressive forces that translate, at the multicellular scale, into the buildup of a mechanical growth-induced pressure, hereafter denoted GIP. GIP decreases cell growth and division of all organisms: bacteria, fungi, plants or mammals[7–12]. However, the mechanisms that control proliferation under GIP remain unknown.…”

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confidence: 99%

Macromolecular crowding limits growth under pressure

Alric

Formosa-Dague

Dague

et al. 2021

Preprint

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Cells that grow in confined spaces eventually build up mechanical compressive stress. This growth-induced pressure (GIP) decreases cell growth. GIP is important in a multitude of contexts from cancer, to microbial infections, to biofouling, yet our understanding of its origin and molecular consequences remains limited. Here, we combine microfluidic confinement of the yeast Saccharomyces cerevisiae, with rheological measurements using genetically encoded multimeric nanoparticles (GEMs) to reveal that growth-induced pressure is accompanied with an increase in a key cellular physical property: macromolecular crowding. We develop a fully calibrated model that predicts how increased macromolecular crowding hinders protein expression and thus diminishes cell growth. This model is sufficient to explain the coupling of growth rate to pressure without the need for specific molecular sensors or signaling cascades. As molecular crowding is similar across all domains of life, this could be a deeply conserved mechanism of biomechanical feedback that allows environmental sensing originating from the fundamental physical properties of cells.

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confidence: 99%

Macromolecular crowding limits growth under pressure

Alric

Formosa-Dague

Dague

et al. 2021

Preprint

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“…Notably, several studies highlight the contribution of the mTOR pathway in mechanisms of drug resistance [2,52,105,[109][110][111][112][116][117][118]120]. In these mechanisms, mTOR holds a dual role.…”

Section: Discussionmentioning

confidence: 99%

“…As it was recently highlighted in experiments of compressive stress application in pancreatic cancer cells spheroids, increased compressive stress results in reduced drug efficacy. The proposed mechanism suggests that compressive stress reduces cell proliferation; thereby, chemotherapeutic drugs show minimum efficacy against proliferating cells [109]. ECM-attached ovarian cells in 3D cultures are resistant to PI3K/mTOR inhibition.…”

Section: Mtor Targeting and Mechanotransduction Interplay In Anticanc...mentioning

confidence: 99%

mTOR Signaling Components in Tumor Mechanobiology

Gargalionis

Papavassiliou

Basdra

et al. 2022

IJMS

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Mechanistic target of rapamycin (mTOR) is a central signaling hub that integrates networks of nutrient availability, cellular metabolism, and autophagy in eukaryotic cells. mTOR kinase, along with its upstream regulators and downstream substrates, is upregulated in most human malignancies. At the same time, mechanical forces from the tumor microenvironment and mechanotransduction promote cancer cells’ proliferation, motility, and invasion. mTOR signaling pathway has been recently found on the crossroads of mechanoresponsive-induced signaling cascades to regulate cell growth, invasion, and metastasis in cancer cells. In this review, we examine the emerging association of mTOR signaling components with certain protein tools of tumor mechanobiology. Thereby, we highlight novel mechanisms of mechanotransduction, which regulate tumor progression and invasion, as well as mechanisms related to the therapeutic efficacy of antitumor drugs.

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“…Tumor aggregate disorganization induced by PI3Kα inhibitors could allow better cisplatin bioavailability within tumorospheres by breaking the decreasing diffusion gradient from the periphery to the center of these 3D structures (Sant and Johnston, 2017). Tumorosphere dissociation could also decrease the solid stress that builds up in 3D culture (Delarue et al, 2014), which was shown to decrease cell proliferation and chemotherapy efficiency (Rizzuti et al, 2020). Other parameters we could have analyzed are the response to increased liquid pressure (Klymenko et al, 2018) or to shear stress caused by ascites fluid motion in the peritoneal cavity (Rizvi et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The lipid kinase PI3Kα is required for the cohesion and survival of cancer cells disseminated in serous cavities

Thibault

Thole

Basset

et al. 2019

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Running Title 38 -max 40PI3Kα controls tumour cell aggregation SUMMARY (174 WORDS) -MAX 175 WORDSPeritoneal carcinomatosis in ovarian cancer is often associated with ascites. In malignant ascites, tumour isolated cells and cell aggregates were present with a variability in size and numbers.Addition of mesenchymal stem cells, as a model of tumoural stroma, favoured aggregation of tumour cells. Because of the emerging concept that tri-dimensional cell culture could lead to increased resistance to conventional therapies, we investigated the importance of PI3Kα-driven protumourigenic and pro-chemoresistance signal in the formation of 3D model of ovarian cancer ascites. We demonstrated, through the use of selective pharmacological inhibitors of the PI3Kα isoform, the key role of this enzyme in the formation and maintenance of multicellular aggregates from ovarian origin. This role did not depend solely on a pro-survival activity of PI3Kα, but could be linked to changes in cell/cell adhesion. Finally, PI3Kα-selective inhibitors were also equally efficient in the presence of cisplatin. We hence identified a signaling pathway of interest for the 2 treatment of advanced ovarian cancer, which could limit the progression of this poor prognosis cancer by ascites cancer cell dissemination.

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Mechanical Control of Cell Proliferation Increases Resistance to Chemotherapeutic Agents

Cited by 46 publications

References 40 publications

Macromolecular crowding limits growth under pressure

Macromolecular crowding limits growth under pressure

mTOR Signaling Components in Tumor Mechanobiology

The lipid kinase PI3Kα is required for the cohesion and survival of cancer cells disseminated in serous cavities

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