Mechanobiology in oncology: basic concepts and clinical prospects.

The interplay between genetic transformations, biochemical communications, and physical interactions is crucial in cancer progression. Metastasis, a leading cause of cancer-related deaths, involves a series of steps, including invasion, intravasation, circulation survival, and extravasation. Mechanical alterations, such as changes in stiffness and morphology, play a significant role in all stages of cancer initiation and dissemination. Accordingly, a better understanding of cancer mechanobiology can help in the development of novel therapeutic strategies. Targeting the physical properties of tumours and their microenvironment presents opportunities for intervention. Advancements in imaging techniques and lab-on-a-chip systems enable personalized investigations of tumor biomechanics and drug screening. Investigation of the interplay between genetic, biochemical, and mechanical factors, which is of crucial importance in cancer progression, offers insights for personalized medicine and innovative treatment strategies.

Stromal cells regulate mechanics of tumour spheroid.

The remarkable contractility and force generation ability exhibited by cancer cells empower them to overcome the resistance and steric hindrance presented by a three-dimensional, interconnected matrix. Cancer cells disseminate by actively remodelling and deforming their extracellular matrix (ECM). The process of tumour growth and its ECM remodelling have been extensively studied, but the effect of the cellular tumour microenvironment (TME) has been ignored in most studies that investigated tumour-cell-mediated ECM deformations and realignment. This study reports the integration of stromal cells in spheroid contractility assays that impacts the ECM remodelling and invasion abilities of cancer spheroids. To investigate this, we developed a novel multilayer in vitro assay that incorporates stromal cells and quantifies the contractile deformations that tumour spheroids exert on the ECM. We observed a negative correlation between the spheroid invasion potential and the levels of collagen deformation. The presence of stromal cells significantly increased cancer cell invasiveness and altered the cancer cells' ability to deform and realign collagen gel, due to upregulation of proinflammatory cytokines. Interestingly, this was observed consistently in both metastatic and non-metastatic cancer cells. Our findings contribute to a better understanding of the vital role played by the cellular TME in regulating the invasive outgrowth of cancer cells and underscore the potential of utilising matrix deformation measurements as a biophysical marker for evaluating invasiveness and informing targeted therapeutic opportunities.

Corrigendum: Hippocampus of the APPNL-G-F mouse model of Alzheimer's disease exhibits region-specific tissue softening concomitant with elevated astrogliosis.

[This corrects the article DOI: 10.3389/fnagi.2023.1212212.].

Hippocampus of the APPNL-G-F mouse model of Alzheimer's disease exhibits region-specific tissue softening concomitant with elevated astrogliosis.

Widespread neurodegeneration, enlargement of cerebral ventricles, and atrophy of cortical and hippocampal brain structures are classic hallmarks of Alzheimer's disease (AD). Prominent macroscopic disturbances to the cytoarchitecture of the AD brain occur alongside changes in the mechanical properties of brain tissue, as reported in recent magnetic resonance elastography (MRE) measurements of human brain mechanics. Whilst MRE has many advantages, a significant shortcoming is its spatial resolution. Higher resolution "cellular scale" assessment of the mechanical alterations to brain regions involved in memory formation, such as the hippocampus, could provide fresh new insight into the etiology of AD. Characterization of brain tissue mechanics at the cellular length scale is the first stepping-stone to understanding how mechanosensitive neurons and glia are impacted by neurodegenerative disease-associated changes in their microenvironment. To provide insight into the microscale mechanics of aging brain tissue, we measured spatiotemporal changes in the mechanical properties of the hippocampus using high resolution atomic force microscopy (AFM) indentation tests on acute brain slices from young and aged wild-type mice and the APPNL-G-F mouse model. Several hippocampal regions in APPNL-G-F mice are significantly softer than age-matched wild-types, notably the dentate granule cell layer and the CA1 pyramidal cell layer. Interestingly, regional softening coincides with an increase in astrocyte reactivity, suggesting that amyloid pathology-mediated alterations to the mechanical properties of brain tissue may impact the function of mechanosensitive astrocytes. Our data also raise questions as to whether aberrant mechanotransduction signaling could impact the susceptibility of neurons to cellular stressors in their microenvironment.

Emergent mechanical control of vascular morphogenesis.

Vascularization is driven by morphogen signals and mechanical cues that coordinately regulate cellular force generation, migration, and shape change to sculpt the developing vascular network. However, it remains unclear whether developing vasculature actively regulates its own mechanical properties to achieve effective vascularization. We engineered tissue constructs containing endothelial cells and fibroblasts to investigate the mechanics of vascularization. Tissue stiffness increases during vascular morphogenesis resulting from emergent interactions between endothelial cells, fibroblasts, and ECM and correlates with enhanced vascular function. Contractile cellular forces are key to emergent tissue stiffening and synergize with ECM mechanical properties to modulate the mechanics of vascularization. Emergent tissue stiffening and vascular function rely on mechanotransduction signaling within fibroblasts, mediated by YAP1. Mouse embryos lacking YAP1 in fibroblasts exhibit both reduced tissue stiffness and develop lethal vascular defects. Translating our findings through biology-inspired vascular tissue engineering approaches will have substantial implications in regenerative medicine.

Longitudinal association between saliva and hair cortisol concentration: A systematic comparison.

Cortisol assays from hair have become increasingly common in psychoneuroendocrinological research as indicators of long-term output relevant to stress and health outcomes. Comparisons of hair cortisol concentration (HCC) with salivary samples have produced mixed findings, and it remains unclear which aspects of the diurnal salivary profile correspond most closely to HCC, and what time intervals between saliva and hair sampling are most relevant, taking the rate of hair growth into account. This longitudinal study aimed to evaluate the correspondence between HCC and parameters of total salivary cortisol output in the morning (CARauc and CARi) and during the rest of the day excluding the early morning period (DAYauc), by systematically studying three time periods - two weeks, four weeks, and six weeks - before hair sampling. At each time period, 54 female university students (mean age: 20.85 ± 1.16 years) provided three saliva cortisol samples on day 1 at 11 am, 3 pm, at bedtime, then two samples the following day on waking and 30 min after awakening. Hair strand collection (1 cm nearest the scalp) took place two weeks after the last saliva sample. Results of multivariable regressions indicate that HCC was consistently associated with DAYauc for all three time periods and with the aggregate DAYauc across days after adjusting for age, body mass index, smoking, oral contraceptive use, hair washing frequency and hair treatments. The strongest associations were found for DAYauc two weeks before hair sampling (ß = 0.578, p < 0.001) and the aggregated DAYauc across all three time periods (ß = 0.596, p < 0.001), although the confidence intervals overlapped those for four and six week analyses. There was no significant association between HCC and either CARauc or CARi. Our study confirms that hair cortisol could be a reliable retrospective biomarker of basal and long-term cortisol output secretion at least up to six weeks earlier. The results contribute to a better understanding of the different associations between HCC and salivary cortisol in the morning and the rest of the day, while also having implications for the use of HCC as an outcome measure in intervention and treatment research.

Endothelium and Subendothelial Matrix Mechanics Modulate Cancer Cell Transendothelial Migration.

Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and ECM, particularly at the primary tumor site, very little is known about the mechanical properties of endothelial cells and the subendothelial ECM and how they contribute to the extravasation process. Here, an integrated experimental and theoretical framework is developed to investigate the mechanical crosstalk between TCs, endothelium and subendothelial ECM during in vitro cancer cell extravasation. It is found that cancer cell actin-rich protrusions generate complex push-pull forces to initiate and drive TEM, while transmigration success also relies on the forces generated by the endothelium. Consequently, mechanical properties of the subendothelial ECM and endothelial actomyosin contractility that mediate the endothelial forces also impact the endothelium's resistance to cancer cell transmigration. These results indicate that mechanical features of distant tissues, including force interactions between the endothelium and the subendothelial ECM, are key determinants of metastatic organotropism.

Associations between hair cortisol concentration, income, income dynamics and status incongruity in healthy middle-aged women.

A body of research demonstrates that financial disadvantage is associated with general health inequalities and higher mortality rates. Most studies make use of cross-sectional analyses, although income can also be viewed as a dynamic concept. The use of endocrine-markers as proxies for health can provide information about the pathways involved in these associations. Hair cortisol analysis has been developed as a method for assessing sustained cortisol output as it provides an estimate of cumulative cortisol secretion over a prolonged time. The present study assessed income and income trajectory over a 4-year period in 164 working women (aged 26-65) in relation to hair cortisol in a longitudinal design. A negative association between hair cortisol and concurrent income was found (p=0.025) and hair cortisol and changes in income over 4 years (p<0.001), after adjustment for age, BMI, smoking status, hair treatment and country. Status incongruity, a mismatch between educational status and income group, was related to higher cortisol levels compared with status congruity (p=0.009). These findings suggest that psychoneuroendocrinological pathways might partially explain the relationship between lower socio-economic status and adverse health outcomes. Future longitudinal research using hair cortisol analysis is warranted to clarify the time course of social mobility in relation to long-term cortisol, to investigate other underlying psychosocial factors implicated in these associations, and to determine the exact health implications of the neuroendocrine perturbations in individuals with limited economic resources.