Mechanical properties of human tumour tissues and their implications for cancer development.

The mechanical properties of cells and tissues help determine their architecture, composition and function. Alterations to these properties are associated with many diseases, including cancer. Tensional, compressive, adhesive, elastic and viscous properties of individual cells and multicellular tissues are mostly regulated by reorganization of the actomyosin and microtubule cytoskeletons and extracellular glycocalyx, which in turn drive many pathophysiological processes, including cancer progression. This Review provides an in-depth collection of quantitative data on diverse mechanical properties of living human cancer cells and tissues. Additionally, the implications of mechanical property changes for cancer development are discussed. An increased knowledge of the mechanical properties of the tumour microenvironment, as collected using biomechanical approaches capable of multi-timescale and multiparametric analyses, will provide a better understanding of the complex mechanical determinants of cancer organization and progression. This information can lead to a further understanding of resistance mechanisms to chemotherapies and immunotherapies and the metastatic cascade.

A Professional Development Workshop: Applying the Race and Culture Guide to Reduce Bias in Medical Teaching Cases.

Introduction: Clinical teaching cases are a cornerstone of health professions education programs, but cases historically have lacked diversity and have the potential to reinforce essentialism. In this article, we describe the creation, implementation, and feasibility assessment of a professional development workshop aimed at integrating an existing bias reduction tool into discussion and revision of teaching cases. Methods: Six 60-minute workshops were held introducing "The Race and Culture Guide for Editors of Teaching Cases" to different health profession education programs wherein all participants worked in small groups to critique and edit two sample teaching cases. To assess initial feasibility, facilitators completed a facilitator evaluation survey to capture experiences after the first three workshops. Due to positive feedback, workshops were continued, and participants completed a participant evaluation survey to understand learner impact. Results: Facilitators (n=6) identified the workshop as addressing an important need, highlighted the value in small-group format, and noted their ability to facilitate future sessions. Participants (n=18) rated the workshop as useful, effective at challenging biases, and would recommend the workshop to others. Conclusion: The purpose of this study was to understand the feasibility of implementing a discussion-based workshop integrating a bias reduction tool. Initial feasibility and acceptability assessments demonstrate that this workshop.

Sociodemographic factors and research experience impact MD-PhD program acceptance.

The 2014 NIH Physician-Scientist Workforce Working Group predicted a future shortage of physician-scientists. Subsequent studies have highlighted disparities in MD-PhD admissions based on race, income, and education. Our analysis of data from the Association of American Medical Colleges covering 2014-2021 (15,156 applicants and 6,840 acceptees) revealed that acceptance into US MD-PhD programs correlates with research experience, family income, and research publications. The number of research experiences associated with parental education and family income. Applicants were more likely to be accepted with a family income greater than $50,000 or with one or more publications or presentations. Applicants were less likely to be accepted if they had parents without a graduate degree, were Black/African American, were first-generation college students, or were reapplicants, irrespective of the number of research experiences, publications, or presentations. These findings underscore an admissions bias that favors candidates from affluent and highly educated families, while disadvantaging underrepresented minorities.

Septins provide microenvironment sensing and cortical actomyosin partitioning in motile amoeboid T lymphocytes.

The all-terrain motility of lymphocytes in tissues and tissue-like gels is best described as amoeboid motility. For amoeboid motility, lymphocytes do not require specific biochemical or structural modifications to the surrounding extracellular matrix. Instead, they rely on changing shape and steric interactions with the microenvironment. However, the exact mechanism of amoeboid motility remains elusive. Here, we report that septins participate in amoeboid motility of T cells, enabling the formation of F-actin and α-actinin-rich cortical rings at the sites of cell cortex-indenting collisions with the extracellular matrix. Cortical rings compartmentalize cells into chains of spherical segments that are spatially conformed to the available lumens, forming transient "hourglass"-shaped steric locks onto the surrounding collagen fibers. The steric lock facilitates pressure-driven peristaltic propulsion of cytosolic content by individually contracting cell segments. Our results suggest that septins provide microenvironment-guided partitioning of actomyosin contractility and steric pivots required for amoeboid motility of T cells in tissue-like microenvironments.

Septins Enable T Cell Contact Guidance via Amoeboid-Mesenchymal Switch.

Lymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septin's GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues.

Mechanical Counterbalance of Kinesin and Dynein Motors in a Microtubular Network Regulates Cell Mechanics, 3D Architecture, and Mechanosensing.

Microtubules (MTs) and MT motor proteins form active 3D networks made of unstretchable cables with rod-like bending mechanics that provide cells with a dynamically changing structural scaffold. In this study, we report an antagonistic mechanical balance within the dynein-kinesin microtubular motor system. Dynein activity drives the microtubular network inward compaction, while isolated activity of kinesins bundles and expands MTs into giant circular bands that deform the cell cortex into discoids. Furthermore, we show that dyneins recruit MTs to sites of cell adhesion, increasing the topographic contact guidance of cells, while kinesins antagonize it via retraction of MTs from sites of cell adhesion. Actin-to-microtubule translocation of septin-9 enhances kinesin-MT interactions, outbalances the activity of kinesins over that of dyneins, and induces the discoid architecture of cells. These orthogonal mechanisms of MT network reorganization highlight the existence of an intricate mechanical balance between motor activities of kinesins and dyneins that controls cell 3D architecture, mechanics, and cell-microenvironment interactions.