Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission

Zhang, Sue; Grifno, Gabrielle; Passaro, Rachel; Regan, Kathryn; Zheng, Siyi; Hadzipasic, Muhamed; Banerji, Rohin; O’Connor, Logan; Chu, Vinson; Kim, Sung Yeon; Yang, Jiarui; Shi, Linzheng; Karrobi, Kavon; Roblyer, Darren; Grinstaff, Mark W.; Nia, Hadi T.

doi:10.1038/s41551-023-01080-8

Cited by 17 publications

(9 citation statements)

References 86 publications

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“…Second, as force sensors, they enable the accurate evaluation of stresses at the cellular level via analysis of their deformation (Taubenberger et al, 2019 ; Träber et al, 2019 ; Zhang et al, 2023). By measuring the mechanical stress that these near-elastic objects encounter at various intravascular arrest sites and comparing their deformation to the ones of viscoelastic tumor cells, we pinpointed to the importance of viscosity in controlling CTC arrest.…”

Section: Discussionmentioning

confidence: 99%

Cell viscosity influences hematogenous dissemination and metastatic extravasation of tumor cells

Gensbittel,

Follain,

Bochler

et al. 2024

Preprint

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Metastases arise from a multi-step process during which tumor cells change their mechanics in response to microenvironmental cues. While such mechanical adaptability could influence metastatic success, how tumor cell mechanics directly impacts intravascular behavior of circulating tumor cells (CTCs) remains poorly understood. In the present study, we demonstrate how the deformability of CTCs affects hematogenous dissemination and identify the mechanical profiles that favor metastatic extravasation. Combining intravital microscopy with CTC-mimicking elastic beads and mechanically-tuned tumor cells, we demonstrate that the inherent properties of circulating objects dictate their ability to enter constraining vessels. We identify cellular viscosity as the key property that governs CTC circulation and arrest patterns. We further demonstrate that cellular viscosity is required for efficient extravasation and find that properties that favor extravasation and subsequent metastatic outgrowth can be opposite. Altogether, we identify CTC viscosity as a key biomechanical parameter that shapes several steps of metastasis.

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Section: Discussionmentioning

confidence: 99%

Cell viscosity influences hematogenous dissemination and metastatic extravasation of tumor cells

Gensbittel,

Follain,

Bochler

et al. 2024

Preprint

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“…Potential solutions are the recently developed methods where a sensor of solid stress, e.g. deformable microgels, is embedded in the organ of interest ( 18 , 36–39 ). While these methods are either minimally invasive during the injection of the sensor ( 39 ), the sensor can potentially be embedded during the early development as in the case of tumor growth ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

“…deformable microgels, is embedded in the organ of interest ( 18 , 36–39 ). While these methods are either minimally invasive during the injection of the sensor ( 39 ), the sensor can potentially be embedded during the early development as in the case of tumor growth ( 18 ). Developing a method to noninvasively study solid stresses in healthy brain of animals and human remains an unmet need with immense potential for uncovering the role of mechanical forces in brain development and aging.…”

Section: Discussionmentioning

confidence: 99%

“…Residual solid stresses in biological tissues were first identified in arteries, where changes in systemic pressure can trigger asymmetrical growth in the inner and outer layers ( 8 ), and later also found during rapid growth, a defining feature of organogenesis ( 5 , 7–10 ) and tumor growth ( 1 , 3 , 11 , 12 ). During tumor growth, residual solid stresses were shown to be a key contributor in tumor progression ( 13 , 14 ), immune evasion ( 15 ), and treatment resistance by directly compressing the blood and lymphatic vessels ( 12 , 16 , 17 ) or directly compressing the cancer cells ( 18 , 19 ). More recently, we showed that solid stresses applied on the neurons surrounding brain tumors causes neuronal death ( 20 , 21 ), which can be protected by neuroprotective strategies such as the use of lithium ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

“…Our limited understanding of the solid stress-associated mechanobiology in the brain is partially due to challenges in directly mapping these stresses. Unlike stiffness, a mechanical property which has been successfully demonstrated as a key player in the brain health and disease ( 22–25 ), measuring the solid stress requires either mechanical intervention to relax the existing stresses ( 3 , 20 , 35 ) or embedding microgels to estimate the stresses ( 18 , 36–39 ).…”

Section: Introductionmentioning

confidence: 99%

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Alteration of mechanical stresses in the murine brain by age and hemorrhagic stroke

Zheng,

Banerji,

LeBourdais

et al. 2024

PNAS Nexus

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Residual mechanical stresses, also known as solid stresses, emerge during rapid differential growth or remodeling of tissues, as observed in morphogenesis and tumor growth. While residual stresses typically dissipate in most healthy adult organs, as the growth rate decreases, high residual stresses have been reported in mature, healthy brains. However, the origins and consequences of residual mechanical stresses in the brain across health, aging, and disease remain poorly understood. Here, we utilized and validated a previously developed method to map residual mechanical stresses in the brains of mice across three age groups: 5–7 days, 8–12 weeks, and 22 months. We found that residual solid stress rapidly increases from 5–7 days to 8–12 weeks and remains high in mature 22 months mice brains. Three-dimensional mapping revealed unevenly distributed residual stresses from the anterior to posterior coronal brain sections. Since the brain is rich in negatively charged hyaluronic acid, we evaluated the contribution of charged extracellular matrix (ECM) constituents in maintaining solid stress levels. We found that lower ionic strength leads to elevated solid stresses, consistent with its unshielding effect and the subsequent expansion of charged ECM components. Lastly, we demonstrated that hemorrhagic stroke, accompanied by loss of cellular density, resulted in decreased residual stress in the murine brain. Our findings contribute to a better understanding of spatiotemporal alterations of residual solid stresses in healthy and diseased brains, a crucial step toward uncovering the biological and immunological consequences of this understudied mechanical phenotype in the brain.

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A Hierarchical Mechanotransduction System: From Macro to Micro

Cao,

Tian,

Tian

et al. 2023

Advanced Science

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Mechanotransduction is a strictly regulated process whereby mechanical stimuli, including mechanical forces and properties, are sensed and translated into biochemical signals. Increasing data demonstrate that mechanotransduction is crucial for regulating macroscopic and microscopic dynamics and functionalities. However, the actions and mechanisms of mechanotransduction across multiple hierarchies, from molecules, subcellular structures, cells, tissues/organs, to the whole‐body level, have not been yet comprehensively documented. Herein, the biological roles and operational mechanisms of mechanotransduction from macro to micro are revisited, with a focus on the orchestrations across diverse hierarchies. The implications, applications, and challenges of mechanotransduction in human diseases are also summarized and discussed. Together, this knowledge from a hierarchical perspective has the potential to refresh insights into mechanotransduction regulation and disease pathogenesis and therapy, and ultimately revolutionize the prevention, diagnosis, and treatment of human diseases.

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Intravital measurements of solid stresses in tumours reveal length-scale and microenvironmentally dependent force transmission

Cited by 17 publications

References 86 publications

Cell viscosity influences hematogenous dissemination and metastatic extravasation of tumor cells

Cell viscosity influences hematogenous dissemination and metastatic extravasation of tumor cells

Alteration of mechanical stresses in the murine brain by age and hemorrhagic stroke

A Hierarchical Mechanotransduction System: From Macro to Micro

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