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Macrophage infiltration in mammary tumors is associated with enhanced tumor progression, metastasis, and poor clinical outcome, and considered as target for therapeutic intervention. By using different genetic mouse models, the authors show that ablation of the tyrosine kinase PYK2, either in breast cancer cells, only in the tumor microenvironment, or in both, markedly reduces the number of infiltrating tumor macrophages and concomitantly inhibits tumor angiogenesis and tumor growth. Strikingly, PYK2 ablation only in macrophages is sufficient to induce similar effects. These phenotypic changes are associated with reduced monocyte recruitment and a substantial decrease in tumor‐associated macrophages (TAMs). Mechanistically, the authors show that PYK2 mediates mutual communication between breast cancer cells and macrophages through critical effects on key receptor signaling. Specifically, PYK2 ablation inhibits Notch1 signaling and consequently reduces CCL2 secretion by breast cancer cells, and concurrently reduces the levels of CCR2, CXCR4, IL‐4Rα, and Stat6 activation in macrophages. These bidirectional effects modulate monocyte recruitment, macrophage polarization, and tumor angiogenesis. The expression of PYK2 is correlated with infiltrated macrophages in breast cancer patients, and its effects on macrophage infiltration and pro‐tumorigenic phenotype suggest that PYK2 targeting can be utilized as an effective strategy to modulate TAMs and possibly sensitize breast cancer to immunotherapy. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets. [ABSTRACT FROM AUTHOR]

Die Fähigkeit, Herausforderungen und Probleme im Alltag erfolgreich zu bewältigen, gilt als wesentliche Facette von Resilienz und schützt Heranwachsende während ihrer gesamten Entwicklung. Zwei Möglichkeiten, sozial-kognitive Problemlösefähigkeiten im Vorschulalter zu erfassen, werden methodisch vorgestellt und empirisch mit der häuslichen Lernumwelt in Beziehung gesetzt. Die Daten stammen aus dem Verbundprojekt „Lernunterstützung durch kognitive Aktivierung in inklusiven Kitas (KoAkiK)". The ability to successfully cope with challenges and problems in everyday life is considered an essential facet of resilience and protects children and youths throughout their development. Two ways of capturing social-cognitive problem-solving skills in preschool age will first be methodically presented and then empirically related to the home learning environment. The data originate from the joint project "cognitive activation in inclusive child care centers (KoAkiK)". [ABSTRACT FROM AUTHOR]

Die Fähigkeit, Herausforderungen und Probleme im Alltag erfolgreich zu bewältigen, gilt als wesentliche Facette von Resilienz und schützt Heranwachsende während ihrer gesamten Entwicklung. Zwei Möglichkeiten, sozial-kognitive Problemlösefähigkeiten im Vorschulalter zu erfassen, werden methodisch vorgestellt und empirisch mit der häuslichen Lernumwelt in Beziehung gesetzt. Die Daten stammen aus dem Verbundprojekt „Lernunterstützung durch kognitive Aktivierung in inklusiven Kitas (KoAkiK)". The ability to successfully cope with challenges and problems in everyday life is considered an essential facet of resilience and protects children and youths throughout their development. Two ways of capturing social-cognitive problem-solving skills in preschool age will first be methodically presented and then empirically related to the home learning environment. The data originate from the joint project "cognitive activation in inclusive child care centers (KoAkiK)". [ABSTRACT FROM AUTHOR]

Prediction of drug combinations that effectively target cancer cells is a critical challenge for cancer therapy, in particular for triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype with no effective targeted treatment. As signalling pathway networks critically control cancer cell behaviour, analysis of signalling network activity and crosstalk can help predict potent drug combinations and rational stratification of patients, thus bringing therapeutic and prognostic values. We have previously showed that the non-receptor tyrosine kinase PYK2 is a downstream effector of EGFR and c-Met and demonstrated their crosstalk signalling in basal-like TNBC. Here we applied a systems modelling approach and developed a mechanistic model of the integrated EGFR-PYK2-c-Met signalling network to identify and prioritize potent drug combinations for TNBC. Model predictions validated by experimental data revealed that among six potential combinations of drug pairs targeting the central nodes of the network, including EGFR, c-Met, PYK2 and STAT3, co-targeting of EGFR and PYK2 and to a lesser extent of EGFR and c-Met yielded strongest synergistic effect. Importantly, the synergy in co-targeting EGFR and PYK2 was linked to switch-like cell proliferation-associated responses. Moreover, simulations of patient-specific models using public gene expression data of TNBC patients led to predictive stratification of patients into subgroups displaying distinct susceptibility to specific drug combinations. These results suggest that mechanistic systems modelling is a powerful approach for the rational design, prediction and prioritization of potent combination therapies for individual patients, thus providing a concrete step towards personalized treatment for TNBC and other tumour types. [ABSTRACT FROM AUTHOR]

Efficient wound repair is essential for the maintenance of the integrity of the skin. The repair process is controlled by a variety of growth factors and cytokines, and their abnormal expression or activity can cause healing disorders. Here, we show that wound repair is severely delayed in mice lacking fibroblast growth factor receptors (FGFR) 1 and 2 in keratinocytes. As the underlying mechanism, we identified impaired wound contraction and a delay in re-epithelialization that resulted from impaired keratinocyte migration at the wound edge. Scratch wounding and transwell assays demonstrated that FGFR1/2-deficient keratinocytes had a reduced migration velocity and impaired directional persistence owing to inefficient formation and turnover of focal adhesions. Underlying this defect, we identified a significant reduction in the expression of major focal adhesion components in the absence of FGFR signaling, resulting in a general migratory deficiency. These results identify FGFs as key regulators of keratinocyte migration in wounded skin. [ABSTRACT FROM AUTHOR]

Abstract: Cutaneous wound repair is a tightly regulated and dynamic process involving blood clotting, inflammation, formation of new tissue, and tissue remodeling. Gene expression profiling of mouse and human wounds as well as first proteomics studies have identified a large number of genes and proteins that are up- or downregulated by skin injury, and some of them have been functionally characterized in animal models of wound repair. Among the key regulators of wound repair are growth factors, which control migration, proliferation, differentiation and survival of cells at different stages of the healing process. This review summarizes the results of functional studies performed in mammals that have identified important roles of receptor tyrosine kinases and their ligands in wound repair. [Copyright &y& Elsevier]

The article presents a study on the effect of the epidermal growth factor receptor (EGFR) ligands to the sebaceous glands of a mice. It says that epigen transgenic mice were being generated to determine the biological activities of EGFR. Moreover, the study discovered that the sebaceous glands of the mice enlarged after the EGFR ligand was injected, which means the expansion of the basal undifferentiated cells in the gland.

By 2040, roughly two-thirds of humanity are expected to live in urban areas. As cities expand, humans irreversibly transform natural ecosystems, creating both opportunities and challenges for wildlife. Here, we investigate how the Northern Goshawk ( Accipiter gentilis ) is adjusting to urban environments. We measured a variety of behavioural and ecological parameters in three urban and four rural study sites. City life appeared related to all parameters we measured. Urban female goshawks were overall 21.7 (CI 95% 5.13-130) times more likely to defend their nestlings from humans than rural females. Urban goshawks were 3.64 (CI 95% 2.05-6.66) times more likely to feed on pigeons and had diets exhibiting lower overall species richness and diversity. Urban females laid eggs 12.5 (CI 95% 7.12-17.4) days earlier than rural individuals and were 2.22 (CI 95% 0.984-4.73) times more likely to produce a brood of more than three nestlings. Nonetheless, urban goshawks suffered more from infections with the parasite Trichomonas gallinae , which was the second most common cause of mortality (14.6%), after collisions with windows (33.1%). In conclusion, although city life is associated with significant risks, goshawks appear to thrive in some urban environments, most likely as a result of high local availability of profitable pigeon prey. We conclude that the Northern Goshawk can be classified as an urban exploiter in parts of its distribution., Competing Interests: The authors declare that they have no conflict of interest., (© 2020 The Authors.)

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model ( MMTV-R26 Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor is generated. MMTV-R26 Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26 Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL-XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS 33 RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets., Competing Interests: The authors declare no conflict of interest., (© 2020 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.

Triple-negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with poor prognosis and no effective targeted therapies. EGFR is highly expressed in basal-like TNBC and is considered as a potential therapeutic target. However, EGFR targeting exerts only marginal clinical benefits, possibly due to activation of compensatory signaling pathways, which are frequently associated with HER3 upregulation. Here we show that concomitant targeting of EGFR and the nonreceptor tyrosine kinases PYK2/FAK synergistically inhibits the proliferation of basal-like TNBC cells in vitro and attenuates tumor growth in a mouse xenograft model. Dual targeting of EGFR and PYK2/FAK inhibited complementary key growth and survival pathways mediated by AKT, S6K, STAT3, and ERK1/2 activation. PYK2 inhibition also abrogated HER3 upregulation in response to EGFR antagonists, thereby circumventing HER3-associated drug resistance. Mechanistically, PYK2 inhibition facilitated the proteasomal degradation of HER3 while inducing upregulation of NDRG1 (N-myc downstream regulated 1 gene). NDRG1 enhanced the interaction of HER3 with the ubiquitin ligase NEDD4, while PYK2, which interacts with NEDD4 and HER3, interfered with NEDD4-HER3 binding, suggesting that the PYK2-NDRG1-NEDD4 circuit has a critical role in receptor degradation, drug response, and resistance mechanism. Our studies offer a preclinical proof of concept for a strategy of cotargeting the EGFR and PYK2/FAK kinases to improve TNBC therapy. Cancer Res; 77(1); 86-99. ©2016 AACR., (©2016 American Association for Cancer Research.)

Fibrosis is associated with a variety of skin diseases and causes severe aesthetic and functional impairments. Functional studies in rodents, together with clinical observations, strongly suggest a crucial role of chronic injury and inflammation in the pathogenesis of fibrotic diseases. The phenotype of mice lacking fibroblast growth factor (FGF) receptors 1 and 2 in keratinocytes supports this concept. In these mice, a defect in keratinocytes alone initiated an inflammatory response, which in turn caused keratinocyte hyperproliferation and dermal fibrosis. As the mechanism underlying this phenotype, we identified a loss of FGF-induced expression of claudins and occludin, which caused abnormalities in tight junctions with concomitant deficits in epidermal barrier function. This resulted in severe transepidermal water loss and skin dryness. In turn, activation of keratinocytes and epidermal γδ T cells occurred, which produced IL-1 family member 8 and S100A8 and S100A9. These cytokines attracted immune cells and activated fibroblasts, resulting in a double paracrine loop through production of keratinocyte mitogens by dermal cells. In addition, a profibrotic response was induced in fibroblasts. Our results highlight the importance of an intact epidermal barrier for the prevention of inflammation and fibrosis and the role of chronic inflammation in the pathogenesis of fibrotic diseases.