Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Forster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micro-patterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow-induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy

Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy

Inhibitor of Differentiation 4 (ID4) represses mammary myoepithelial differentiation via inhibition of HEB.

Inhibitor of differentiation (ID) proteins dimerize with basic HLH (bHLH) transcription factors, repressing transcription of lineage-specification genes across diverse cellular lineages. ID4 is a key regulator of mammary stem cells; however, the mechanism by which it achieves this is unclear. Here, we show that ID4 has a cell autonomous role in preventing myoepithelial differentiation of basal cells in mammary organoids and in vivo. ID4 positively regulates proliferative genes and negatively regulates genes involved in myoepithelial function. Mass spectrometry reveals that ID4 interacts with the bHLH protein HEB, which binds to E-box motifs in regulatory elements of basal developmental genes involved in extracellular matrix and the contractile cytoskeleton. We conclude that high ID4 expression in mammary basal stem cells antagonizes HEB transcriptional activity, preventing myoepithelial differentiation and allowing for appropriate tissue morphogenesis. Downregulation of ID4 during pregnancy modulates gene regulated by HEB, promoting specialization of basal cells into myoepithelial cells

Двухмоўны слоўнік метафар псіхалагічнай сферы чалавека / В.Ю. Шыманская

Двухмоўны слоўнік метафар псіхалагічнай сферы чалавека адлюстроўвае субстантыўныя сродкі рэпрэзентацыі псіхалагічнай сферы чалавека ў беларускай і англійскай мовах. Аб’ект слоўнікавай сістэматызацыі – субстантыўныя метафары, які ўжываюцца для намінацыі і характарызацыі псіхічных працэсаў, станаў і ўласцівасцей асобы. Слоўнік з’яўляецца даведачнай крыніцай пры вызначэнні семантыкі, ужывальнасці, сінанімічных варыянтаў і перакладу метафар, а таксама пры выбары сродкаў метафарычнай рэпрэзентацыі псіхалогіі чалавека. Рэестр слоўніка складаюць беларускія і англійскія метафары, змешчаныя ў алфавітным парадку. У слоўніку пададзена 490 беларускіх і 548 англійскіх метафар псіхалагічнай сферы чалавека, да кожнай з якіх прыведзена да 25 сінанімічных і эквівалентных метафар. У агульны рэестр слоўніка, а таксама ў рэестр сінанімічных і эквівалентных метафар уключаны 142 беларускія і 105 англійскіх патэнцыяльных моўных метафар. Слоўнік арыентаваны на шырокае кола карыстальнікаў – філолагаў, выкладчыкаў, пісьменнікаў, перакладчыкаў, усіх, хто вывучае беларускую і англійскую мовы, цікавіцца вобразнымі сродкамі рэпрэзентацыі псіхалагічнай сферы чалавека ў мове

Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple\ua0negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC