Ontology highlight
ABSTRACT:
PROVIDER: PRJNA471134 | ENA |
REPOSITORIES: ENA
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with both an extremely poor prognosis and response to conventional chemotherapy. Identifying novel biological vulnerabilities is therefore critical in the development of more effective therapies. By using patient-derived organoids and murine genetic models, we developed a pipeline for identifying biologically active deubiquitylases (DUBs) with activity-based proteomics, coupled with a loss-of-function genetic screen in organoids. We found that ubiquitin specific protease 25 (USP25) is indispensable for PDAC progression. Compared with normal pancreatic tissue, USP25 was highly expressed and active in murine PDAC tumours and in primary human PDAC samples. Silencing of Usp25/USP25 led to reduced tumour organoid formation and viability, and transcriptional profiling revealed that USP25 is a regulator of hypoxia, glycolysis and HIF-1 signalling pathways. Mechanistically, we found that USP25 directly interacts with HIF-1 and that its deubiquitylase activity regulates HIF-1 protein stability, nuclear translocation and transcriptional activity. Moreover, treatment with a novel USP25 inhibitor resulted in a dramatic loss of murine and patient-derived organoid viability, HIF-1 signalling, and consequently induced substantial regression of murine and human organoid-derived xenografts in vivo. Thus, USP25 is a promising therapeutic target for the treatment of human PDAC.
2022-05-19 | PXD023424 | Pride
Project description:Deubiquitylating enzymes (DUBs) play an essential role in targeted protein degradation and represent an emerging therapeutic paradigm in cancer. However, their therapeutic potential in pancreatic ductal adenocarcinoma (PDAC) has not been explored. Here, we developed a DUB discovery pipeline, combining activity-based proteomics with a loss-of-function genetic screen in patient-derived PDAC organoids and murine genetic models. This approach identified USP25 as a master regulator of PDAC growth and maintenance. Genetic and pharmacological USP25 inhibition resulted in potent growth impairment in PDAC organoids, while normal pancreatic organoids were insensitive, and caused dramatic regression of patient-derived xenografts. Mechanistically, USP25 deubiquitinated and stabilised the HIF-1a transcription factor. PDAC is characterised by a severely hypoxic microenvironment, and USP25 depletion abrogated HIF-1a transcriptional activity and impaired glycolysis, inducing PDAC cell death in the tumor hypoxic core. Thus, the USP25/HIF-1a axis is an essential mechanism of metabolic reprogramming and survival in PDAC, which can be therapeutically exploited.
2022-03-01 | GSE166077 | GEO
Project description:Patient-derived endometrial cancer organoids. The data was used to compare gene expression profile between organoids, and to explore whether an organoid-derived gene signature could predict disease outcomes in independent patient cohorts.
2021-07-16 | E-MTAB-10664 | biostudies-arrayexpress
Project description:Therapy resistance and metastatic processes in prostate cancer remain undefined, due to lack of experimental models that mimic different disease stages. This project aims to perform transcriptomic profiling of novel PCa patient-derived xenograft and organoids models.
| EGAS00001004675 | EGA
Project description:With a five-year survival rate of 9%, pancreatic ductal adenocarcinoma (PDAC) the deadliest of all cancers. The rapid mortality makes PDAC difficult to research, and inspires a resolve to create reliable, tractable cellular models for preclinical cancer research. PDAC organoids are increasing used to model PDAC as they maintain the differentiation status, molecular and genomic signatures of the original tumour. In this paper, we present novel methodologies and experimental approaches to develop PDAC organoids from PDX tumours, and the simultaneous development of matched primary cell lines. Moreover, we also identify a method of recapitulating primary cell line cultures to organoids (CLOs). We highlight the usefulness of CLOs as PDAC organoid models, as they maintain similar transcriptomic signatures as their matched patient-derived organoids and PDXs. These models provide a manageable, expandable in vitro resource for downstream applications such as high throughput screening, functional genomics, and tumour microenvironment studies.
2020-02-05 | GSE144737 | GEO
Project description:We investigated the transcriptomic differences of multi-stroma flow-sorted from cocultures with murine pancreatitis (P)-derived organoids, PDAC organoids, or PDAC organoids following initial coculture with P organoids (ie P-to-PDAC or sequential).
2026-07-02 | GSE329640 | GEO
Project description:BACKGROUND & AIMS: The mechanisms of peritoneal dissemination in pancreatic ductal adenocarcinoma (PDAC) remain unclear partly owing to the lack of patient-derived models that recapitulate this process. This study aimed to establish an orthotopic model of PDAC peritoneal dissemination and to uncover the transcriptional and regulatory programs underlying this process. METHODS: Organoids were established from primary pancreatic tumors and malignant effusions of patients with PDAC and orthotopically transplanted into the pancreas of immunodeficient mice to generate patient-derived orthotopic xenograft (PDOX) models. Subsequently, the organoids were rederived from pancreatic and peritoneal lesions of a representative model (PDOX12) and orthotopically reimplanted to assess the dissemination capacity. Single-nucleus RNA sequencing (snRNA-seq) and single-cell ATAC sequencing (scATAC-seq) were performed to analyze the tumors from these models. RESULTS: The organoids that were derived from malignant effusions reproducibly generated peritoneal metastases after orthotopic implantation. To dissect this process more precisely, we focused on one representative model (PDOX12) and rederived organoids from its pancreatic and peritoneal lesions. These organoids generated matched PDOX models that differed only in dissemination potential when reimplanted orthotopically. The results of snRNA-seq revealed a distinct subpopulation enriched in the high-dissemination model, which was characterized by the coordinated activation of genes involved in cytoskeletal dynamics, extracellular matrix remodeling, and plasticity-related signaling—suggesting a dissemination-primed state. Integration with scATAC-seq identified STAT3, SMAD3, and SOX2 as potential upstream regulators of this gene program. CONCLUSIONS: This study established PDOX models that isolate the peritoneal dissemination phenotype and reveal the transcriptional and regulatory programs driving this process.
2026-03-25 | GSE318412 | GEO
Project description:Gene expression of matched treatment-naive versus FOLFIRINOX-treated PDAC patient-derived organoids
| PRJNA796009 | ENA
Project description:Pancreatic cancer is a disease of urgent unmet clinical need with a 94% death rate, predicted to become the second leading cause of cancer-related death by 2030. Despite increased efforts, effective therapies have not materialised. Here, we uncover a new molecular pathway underpinning pancreatic carcinogenesis, involving TRMT5, an RNA m1G methyltransferase. We show that TRMT5 is overexpressed in primary pancreatic adenocarcinomas (PDACs), and its expression is associated with worse patient survival. High levels of TRMT5 expression positively correlate with the tumorigenic capacity of pancreatic cell lines and of human pancreatic cancer organoids. Using an unbiased multiple screening approach, we identify a new axis involving TRMT5 and Nestin (NES) in pancreatic cancer and define NES mRNA as a substrate of TRMT5. We demonstrate that NES expression, a key cancer regulator, rescues the growth defect of TRMT5 depleted PDAC cells. We pinpoint a site of TRMT5-mediated m1G modification to a G-quadruplex structure within the protein coding region of NES mRNA. Functionally, m1G destabilizes the G-quadruplex structure to promote translation of NES. Finally, we demonstrate that TRMT5 is essential for the metastatic capacity of PDAC cells, significantly promotes the growth of patient-derived PDAC organoids and increases the survival rate of PDAC patient-derived xenografts. Our findings establish the TRMT5/NES axis as a new vulnerability in PDAC and they provide the foundation for innovative combinatorial clinical approaches, targeting an RNA-modification pathway in pancreatic cancer.
2026-05-04 | GSE297264 | GEO
Project description:Pancreatic cancer is a disease of urgent unmet clinical need with a 94% death rate, predicted to become the second leading cause of cancer-related death by 2030. Despite increased efforts, effective therapies have not materialised. Here, we uncover a new molecular pathway underpinning pancreatic carcinogenesis, involving TRMT5, an RNA m1G methyltransferase. We show that TRMT5 is overexpressed in primary pancreatic adenocarcinomas (PDACs), and its expression is associated with worse patient survival. High levels of TRMT5 expression positively correlate with the tumorigenic capacity of pancreatic cell lines and of human pancreatic cancer organoids. Using an unbiased multiple screening approach, we identify a new axis involving TRMT5 and Nestin (NES) in pancreatic cancer and define NES mRNA as a substrate of TRMT5. We demonstrate that NES expression, a key cancer regulator, rescues the growth defect of TRMT5 depleted PDAC cells. We pinpoint a site of TRMT5-mediated m1G modification to a G-quadruplex structure within the protein coding region of NES mRNA. Functionally, m1G destabilizes the G-quadruplex structure to promote translation of NES. Finally, we demonstrate that TRMT5 is essential for the metastatic capacity of PDAC cells, significantly promotes the growth of patient-derived PDAC organoids and increases the survival rate of PDAC patient-derived xenografts. Our findings establish the TRMT5/NES axis as a new vulnerability in PDAC and they provide the foundation for innovative combinatorial clinical approaches, targeting an RNA-modification pathway in pancreatic cancer.
2026-05-04 | GSE297265 | GEO