Differential Mechanical Response of Mesenchymal Stem Cells and Fibroblasts to Tumor-Secreted Soluble Factors

The progression of neoplastic malignancies is a complex process resulting not only from the accumulation of mutations within tumor cells, but also modulation of the tumor microenvironment. Recent advances have shown that the recruitment and subsequent heterotypic interactions of stromal cells—including fibroblasts and bone marrow-derived mesenchymal stem cells (MSCs)—are crucial for carcinogenesis. Though extensive work has been done analyzing the signals that recruit these cells, the governing mechanical properties have not been fully investigated. Here, we report that despite their initial similarities, MSCs respond not only faster but also more dramatically to pro-migratory tumor-secreted soluble factors. Utilizing multiple particle tracking microrheology to probe the cytoskeletal mechanical properties, we show that MSCs stiffen completely within one hour, three times faster than fibroblasts. In addition, unlike fibroblasts, MSCs exposed to tumor-secreted soluble factors display a functionally different phenotype characterized by morphological elongation, decreased actin stress fiber density, and decreased adhesion. Quantitative real-time PCR indicates these phenomena occur based on differential expression of small GTPases RhoA and Cdc42, but not Rac1. These findings demonstrate a fundamental difference in the recruitment of fibroblasts and MSCs

Clinical and Environment Factors Impacting Malignant Pleural Mesothelioma Prognosis

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A murine preclinical syngeneic transplantation model for breast cancer precision medicine

We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments

Thermal Transport in Micro- and Nanoscale Systems

Small-scale (micro-/nanoscale) heat transfer has broad and exciting range of applications. Heat transfer at small scale quite naturally is influenced – sometimes dramatically – with high surface area-to-volume ratios. This in effect means that heat transfer in small-scale devices and systems is influenced by surface treatment and surface morphology. Importantly, interfacial dynamic effects are at least non-negligible, and there is a strong potential to engineer the performance of such devices using the progress in micro- and nanomanufacturing technologies. With this motivation, the emphasis here is on heat conduction and convection. The chapter starts with a broad introduction to Boltzmann transport equation which captures the physics of small-scale heat transport, while also outlining the differences between small-scale transport and classical macroscale heat transport. Among applications, examples are thermoelectric and thermal interface materials where micro- and nanofabrication have led to impressive figure of merits and thermal management performance. Basic of phonon transport and its manipulation through nanostructuring materials are discussed in detail. Small-scale single-phase convection and the crucial role it has played in developing the thermal management solutions for the next generation of electronics and energy-harvesting devices are discussed as the next topic. Features of microcooling platforms and physics of optimized thermal transport using microchannel manifold heat sinks are discussed in detail along with a discussion of how such systems also facilitate use of low-grade, waste heat from data centers and photovoltaic modules. Phase change process and their control using surface micro-/nanostructure are discussed next. Among the feature considered, the first are microscale heat pipes where capillary effects play an important role. Next the role of nanostructures in controlling nucleation and mobility of the discrete phase in two-phase processes, such as boiling, condensation, and icing is explained in great detail. Special emphasis is placed on the limitations of current surface and device manufacture technologies while also outlining the potential ways to overcome them. Lastly, the chapter is concluded with a summary and perspective on future trends and, more importantly, the opportunities for new research and applications in this exciting field

The Canadian Urban Environmental Health Research Consortium - A protocol for building a national environmental exposure data platform for integrated analyses of urban form and health

Background: Multiple external environmental exposures related to residential location and urban form including, air pollutants, noise, greenness, and walkability have been linked to health impacts or benefits. The Canadian Urban Environmental Health Research Consortium (CANUE) was established to facilitate the linkage of extensive geospatial exposure data to existing Canadian cohorts and administrative health data holdings. We hypothesize that this linkage will enable investigators to test a variety of their own hypotheses related to the interdependent associations of built environment features with diverse health outcomes encompassed by the cohorts and administrative data. Methods: We developed a protocol for compiling measures of built environment features that quantify exposure; vary spatially on the urban and suburban scale; and can be modified through changes in policy or individual behaviour to benefit health. These measures fall into six domains: air quality, noise, greenness, weather/climate, and transportation and neighbourhood factors; and will be indexed to six-digit postal codes to facilitate merging with health databases. Initial efforts focus on existing data and include estimates of air pollutants, greenness, temperature extremes, and neighbourhood walkability and socioeconomic characteristics. Key gaps will be addressed for noise exposure, with a new national model being developed, and for transportation-related exposures, with detailed estimates of truck volumes and diesel emissions now underway in selected cities. Improvements to existing exposure estimates are planned, primarily by increasing temporal and/or spatial resolution given new satellite-based sensors and more detailed national air quality modelling. Novel metrics are also planned for walkability and food environments, green space access and function and life-long climate-related exposures based on local climate zones. Critical challenges exist, for example, the quantity and quality of input data to many of the models and metrics has changed over time, making it difficult to develop and validate historical exposures. Discussion: CANUE represents a unique effort to coordinate and leverage substantial research investments and will enable a more focused effort on filling gaps in exposure information, improving the range of exposures quantified, their precision and mechanistic relevance to health. Epidemiological studies may be better able to explore the common theme of urban form and health in an integrated manner, ultimately contributing new knowledge informing policies that enhance healthy urban living

Utilizing temporal variations in chemotherapeutic response to improve breast cancer treatment efficacy

Though survival rates for women with stage I breast cancer have radically improved, treatment options remain poor for the 40% of women diagnosed with later-stage disease. For these patients, improved chemotherapeutic treatment strategies are critical to eradicate any disseminated tumor cells. Despite many promising new drugs in vitro, most ultimately fail in the clinic. One aspect often lost during testing is in vivo circulation half-lives rarely exceed 24 hours, whereas in vitro studies involve drug exposure for 2-3 days. Here, we show how mimicking these exposure times alters efficacy. Next, using this model we show how drug response is highly time-dependent by extending analysis of cell viability out to two weeks. Variations in response both with feeding and time were dependent on drug mechanism of action. Finally, we show that by implementing this temporal knowledge of drug effects to optimize scheduling of drug administration we are able to regain chemosensitivity in a Carboplatin-resistant cell line

Cytosolic DNA accumulation promotes breast cancer immunogenicity via a STING-independent pathway

Background Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. Recent studies have shown that agents targeting DNA damage response improve the efficacy of ICB and promote cytosolic DNA accumulation. However, recent clinical trials have shown that these agents are associated with hematological toxicities. More effective therapeutic strategies are urgently needed.Methods Primary triple negative breast cancer tumors were stained for cytosolic single-stranded DNA (ssDNA) using multiplex immunohistochemical staining. To increase cytosolic ssDNA, we genetically silenced TREX1. The role of tumor cytosolic ssDNA in promoting tumor immunogenicity and antitumor immune response was evaluated using murine breast cancer models.Results We found the tumorous cytosolic ssDNA is associated with tumor-infiltrating lymphocyte in patients with triple negative breast cancer. TREX1 deficiency triggered a STING-independent innate immune response via DDX3X. Cytosolic ssDNA accumulation in tumors due to TREX1 deletion is sufficient to drastically improve the efficacy of ICB. We further identified a cytosolic ssDNA inducer CEP-701, which sensitized breast tumors to ICB without the toxicities associated with inhibiting DNA damage response.Conclusions This work demonstrated that cytosolic ssDNA accumulation promotes breast cancer immunogenicity and may be a novel therapeutic strategy to improve the efficacy of ICB with minimal toxicities

Characterization of bone marrow isolated MSCs and fibroblasts.

<p>Phenotypic analysis was performed by flow cytometry was performed on adherent bone marrow cells and Swiss 3T3 fibroblasts with positive populations in red given with S.E.M.(A). Purified MSCs differentiated into adipocytes (B) and osteoblasts (C) within 3 weeks in lineage-specific differentiation media as shown both my staining and RT-PCR (scale bar = 100 µm).</p