Similar Datasets
Project description:EMT-driven plasticity prospectively increases cell-cell variability to promote therapeutic adaptation in breast cancer
| PRJNA1098856 | ENA
Project description:One of the most serious issues in modern oncology is the ineffectiveness of treatments in destroying tumours, which leads to tumour recurrence and, ultimately, patient death To investigated this we analyze plasticity of chemotherapy-resistant cells
2024-04-09 | GSE229761 | GEO
Project description:Chemotherapy induces cell plasticity controlling plasticity increases therapeutic response.
| PRJNA955789 | ENA
Project description:Most patients with ovarian cancer (OC) are diagnosed at a late stage when there are very few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or an oncogenic addiction that can be targeted pharmacologically, unlike other types of cancer. Here, we identified protein tyrosine kinase 7 (PTK7) as a potential new therapeutic target in OC following a multiomics approach using genetic and pharmacological interventions. We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-γ (SNCG), SALL2, and PP1γ, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab. Our phosphoproteomics analyses demonstrated that PTK7 modulates cell adhesion and Rho-GTPase signaling to sustain epithelial-mesenchymal transition (EMT) and cell plasticity, which was confirmed by high-content image analysis of 3D models. Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer.
| S-EPMC9386025 | biostudies-literature
Project description:Epithelial-mesenchymal transition (EMT) is strongly implicated in tumor cell invasion and metastasis. EMT is thought to be regulated primarily at the transcriptional level through the repressive activity of EMT transcription factors. However, these classical mechanisms have been parsed out almost exclusively in vitro, leaving questions about the programs driving EMT in physiological contexts. Here, using a lineage-labeled mouse model of pancreatic ductal adenocarcinoma to study EMT in vivo, we found that most tumors lose their epithelial phenotype through an alternative program involving protein internalization rather than transcriptional repression, resulting in a "partial EMT" phenotype. Carcinoma cells utilizing this program migrate as clusters, contrasting with the single-cell migration pattern associated with traditionally defined EMT mechanisms. Moreover, many breast and colorectal cancer cell lines utilize this alternative program to undergo EMT. Collectively, these results suggest that carcinoma cells have different ways of losing their epithelial program, resulting in distinct modes of invasion and dissemination.
| S-EPMC6014628 | biostudies-literature
Project description:Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease-causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.
| S-EPMC8501836 | biostudies-literature
Project description:Genetic variation and phenotypic plasticity are both important to adaptive evolution. However, how they act together on particular traits remains poorly understood. Here, we integrated phenotypic, genomic, and transcriptomic data from two allopatric but closely related congeneric oyster species, Crassostrea angulata from southern/warm environments and Crassostrea gigas from northern/cold environments, to investigate the roles of genetic divergence and plasticity in thermal adaptation. Reciprocal transplantation experiments showed that both species had higher fitness in their native habitats than in non-native environments, indicating strong adaptive divergence. The southern species evolved higher transcriptional plasticity, and the plasticity was adaptive, suggesting that increased plasticity is important for thermal adaptation to warm climates. Genome-wide comparisons between the two species revealed that genes under selection tended to respond to environmental changes and showed higher sequence divergence in noncoding regions. All genes under selection and related to energy metabolism exhibited habitat-specific expression with genes involved in ATP production and lipid catabolism highly expressed in warm/southern habitats, and genes involved in ATP consumption and lipid synthesis were highly expressed in cold/northern habitats. The gene for acyl-CoA desaturase, a key enzyme for lipid synthesis, showed strong selective sweep in the upstream noncoding region and lower transcription in the southern species. These results were further supported by the lower free fatty acid (FFA) but higher ATP content in southern species and habitat, pointing to significance of ATP/FFA trade-off. Our findings provide evidence that noncoding variation and transcriptional plasticity play important roles in shaping energy metabolism for thermal adaptation in oysters.
| S-EPMC8557435 | biostudies-literature
Project description:Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat "browning". This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.
| S-EPMC6567243 | biostudies-literature
Project description:The epithelial-to-mesenchymal transition (EMT) is frequently co-opted by cancer cells to enhance migratory and invasive cell traits. It is a key contributor to heterogeneity, chemoresistance, and metastasis in many carcinoma types, where the intermediate EMT state plays a critical tumor-initiating role. We isolate multiple distinct single-cell clones from the SUM149PT human breast cell line spanning the EMT spectrum having diverse migratory, tumor-initiating, and metastatic qualities, including three unique intermediates. Using a multiomics approach, we identify CBFβ as a key regulator of metastatic ability in the intermediate state. To quantify epithelial-mesenchymal heterogeneity within tumors, we develop an advanced multiplexed immunostaining approach using SUM149-derived orthotopic tumors and find that the EMT state and epithelial-mesenchymal heterogeneity are predictive of overall survival in a cohort of stage III breast cancer. Our model reveals previously unidentified insights into the complex EMT spectrum and its regulatory networks, as well as the contributions of epithelial-mesenchymal plasticity (EMP) in tumor heterogeneity in breast cancer.
| S-EPMC9348802 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is the most lethal breast cancer subgroup, as lack of targeted therapies and drug resistance reduce survival rates. Cellular plasticity enables cells to adapt non-genetically and overcome therapeutic pressure, thereby embodying a critical clinical hurdle. The epithelial-mesenchymal transition (EMT) is an example of phenotypic reprogramming linked to plasticity, drug resistance and metastasis. However, its exact impact on population diversity under therapeutic pressure is unknown. Here, we used single cell transcriptomics to investigate phenotypic diversity dynamics upon drug treatment in two human in vitro models of TNBC plasticity.
2024-12-04 | GSE263729 | GEO