shear-assay-protocol-for-determination-single-cell-material

Shear Assay Protocol for the Determination of Single-Cell Material Properties

Irregular biomechanics are a hallmark of cancer biology subject to extensive study. The mechanical properties of a cell are similar to those of a ...

University of Notre Dame

In this Perspective, we provide our insights and opinions about the contribution-and potential co-regulation-of mechanics and metabolism in incurable breast cancer brain metastasis. Altered metabolic activity can affect cancer metastasis as high glucose supply and demand in the brain microenvironment favors aerobic glycolysis. Similarly, the altered mechanical properties of disseminating cancer cells facilitate migration to and metastatic seeding of the brain, where local metabolites support their progression. Cancer cells in the brain and the brain tumor microenvironment often possess opposing mechanical and metabolic properties compared to extracranial cancer cells and their microenvironment, which inhibit the ease of extravasation and metastasis of these cells outside the central nervous system. We posit that the brain provides a metabolic microenvironment that mechanically reinforces the cellular structure of cancer cells and supports their metastatic growth while restricting their spread from the brain to external organs.

Mechanical and metabolic interplay in the brain metastatic microenvironment.

Immune evasion-a well-established cancer hallmark-is a major barrier to immunotherapy efficacy. While the molecular mechanisms and biological consequences underpinning immune evasion are largely known, the role of tissue mechanical stresses in these processes warrants further investigation. The tumor microenvironment (TME) features physical abnormalities (notably, increased fluid and solid pressures applied both inside and outside the TME) that drive cancer mechanopathologies. Strikingly, in response to these mechanical stresses, cancer cells upregulate canonical immune evasion mechanisms, including epithelial-mesenchymal transition (EMT) and autophagy. Consideration and characterization of the origins and consequences of tumor mechanical stresses in the TME may yield novel strategies to combat immunotherapy resistance. In this Perspective, we posit that tumor mechanical stresses-namely fluid shear and solid stresses-induce immune evasion by upregulating EMT and autophagy. In addition to exploring the basis for our hypothesis, we also identify explicit gaps in the field that need to be addressed in order to directly demonstrate the existence and importance of this biophysical relationship. Finally, we propose that reducing or neutralizing fluid shear stress and solid stress-induced cancer immune escape may improve immunotherapy outcomes.

Do Tumor Mechanical Stresses Promote Cancer Immune Escape?

Cancer initiation and progression drastically alter the microenvironment at the interface between healthy and malignant tissue. This site, termed the peritumor, bears unique physical and immune attributes that together further promote tumor progression through interconnected mechanical signaling and immune activity. In this review, we describe the distinct physical features of the peritumoral microenvironment and link their relationship to immune responses. The peritumor is a region rich in biomarkers and therapeutic targets and thus is a key focus for future cancer research as well as clinical outlooks, particularly to understand and overcome novel mechanisms of immunotherapy resistance.

Meenal Datta

Department of Aerospace and Mechanical Engineering

University of Notre Dame

Shear Assay Protocol for the Determination of Single-Cell Material Properties

Meenal Datta

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Aerospace and Mechanical Engineering

University of Notre Dame

Shear Assay Protocol for the Determination of Single-Cell Material Properties

Department of Aerospace and Mechanical Engineering