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The microenvironment of breast cancer hosts a dynamic cross talk between diverse players of the immune system. While cytotoxic immune cells are equipped to control tumor growth and metastasis, tumor-corrupted immunosuppressive immune cells strive to impair effective immunity and promote tumor progression. Of these, regulatory T cells (Tregs), the gatekeepers of immune homeostasis, emerge as multifaceted players involved in breast cancer. Intriguingly, clinical observations suggest that blood and intratumoral Tregs can have strong prognostic value, dictated by breast cancer subtype. Accordingly, emerging preclinical evidence shows that Tregs occupy a central role in breast cancer initiation and progression and provide critical support to metastasis formation. Here, Tregs are not only important for immune escape but also promote tumor progression independent of their immune regulatory capacity. Combining insights into Treg biology with advances made across the rapidly growing field of immuno-oncology is expected to set the stage for the design of more effective immunotherapy strategies.

Immunotherapy is at the forefront of cancer treatment. The advent of numerous novel approaches to cancer immunotherapy, including immune checkpoint antibodies, adoptive transfer of CAR (chimeric antigen receptor) T cells and TCR (T cell receptor) T cells, NK (natural killer) cells, T cell engagers, oncolytic viruses, and vaccines, is revolutionizing the treatment for different tumor types. Some are already in the clinic, and many others are underway. However, not all patients respond, resistance develops, and as available therapies multiply there is a need to further understand how they work, how to prioritize their clinical evaluation, and how to combine them. For this, animal models have been highly instrumental, and humanized mice models (i.e., immunodeficient mice engrafted with human immune and cancer cells) represent a step forward, although they have several limitations. Here, we review the different humanized models available today, the approaches to overcome their flaws, their use for the evaluation of cancer immunotherapies, and their anticipated evolution as tools to help personalized clinical decision-making.

Activating mutations in KRAS are the hallmark genetic alterations in pancreatic ductal adenocarcinoma (PDAC) and the key drivers of its initiation and progression. Longstanding efforts to develop novel KRAS inhibitors have been based on the assumption that PDAC cells are addicted to activated KRAS, but this assumption remains controversial. In this study, we analyzed the requirement of endogenous Kras to maintain survival of murine PDAC cells, using an inducible shRNA-based system that enables temporal control of Kras expression. We found that the majority of murine PDAC cells analyzed tolerated acute and sustained Kras silencing by adapting to a reversible cell state characterized by differences in cell morphology, proliferative kinetics, and tumor-initiating capacity. While we observed no significant mutational or transcriptional changes in the Kras-inhibited state, global phosphoproteomic profiling revealed significant alterations in cell signaling, including increased phosphorylation of focal adhesion pathway components. Accordingly, Kras-inhibited cells displayed prominent focal adhesion plaque structures, enhanced adherence properties, and increased dependency on adhesion for viability in vitro. Overall, our results call into question the degree to which PDAC cells are addicted to activated KRAS, by illustrating adaptive non-genetic and non-transcriptional mechanisms of resistance to Kras blockade. However, by identifying these mechanisms, our work also provides mechanistic directions to develop combination strategies that can help enforce the efficacy of KRAS inhibitors.

Summary The diversity of mesenchymal cell types in the lung that influence epithelial homeostasis and regeneration is poorly defined. We used genetic lineage tracing, single-cell RNA sequencing, and organoid culture approaches to show that Lgr5 and Lgr6, well-known markers of stem cells in epithelial tissues, are markers of mesenchymal cells in the adult lung. Lgr6+ cells comprise a subpopulation of smooth muscle cells surrounding airway epithelia and promote airway differentiation of epithelial progenitors via Wnt-Fgf10 cooperation. Genetic ablation of Lgr6+ cells impairs airway injury repair in vivo. Distinct Lgr5+ cells are located in alveolar compartments and are sufficient to promote alveolar differentiation of epithelial progenitors through Wnt activation. Modulating Wnt activity altered differentiation outcomes specified by mesenchymal cells. This identification of region- and lineage-specific crosstalk between epithelium and their neighboring mesenchymal partners provides new understanding of how different cell types are maintained in the adult lung., Graphical Abstract, Highlights • Lgr5 and Lgr6 mark mesenchymal cells in adult lungs • Single-cell transcriptome analysis defines mesenchymal heterogeneity • Distinct mesenchymal niches drive airway and alveolar differentiation • Wnt activity affects epithelial differentiation specified by mesenchymal cells, Heterogeneous mesenchymal cell populations in the lung play a central role in epithelial maintenance and alveolar differentiation.

To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences-Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells' regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis.

Changes in histomorphology and some indices of liver and kidney functions were studied in rats administered doses of ethanolic extracts of Datura stramonium leaves. Methods: Four experimental groups of rats were respectively given oral doses of 50mg/kg, 100mg/kg and 200mg/kg of the extract daily for six weeks. Rats were sacrificed at the end of the six weeks and blood samples were collected for biochemical analysis. The livers and kidneys of the rates were harvested for histological studies. Results: The results showed that alanine transaminase (ALT) and bilirubin levels were significantly (P