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Gene expression of matched treatment-naive versus FOLFIRINOX-treated PDAC patient-derived organoids

ABSTRACT: In our study, we aimed to investigate adaptive processes of tumors under treatment and therefore, generated PDAC patient-derived organoids (PDOs) and 2D cell lines before and after chemotherapy. We enrolled a patient with borderline resectable PDAC who received neoadjuvant FOLFIRINOX. Endoscopic fine needle (pre-FFX) and surgical biopsies (post-FFX) were used to generate PDOs and 2D cells. Whole exome sequencing (WES) and RNA sequencing data of the pre-FFX and post-FFX organoids were compared in order to evaluate the genetic landscape and PDAC subtypes. Although transcriptional subtyping classified both PDOs as classical PDAC, gene set enrichment analysis (GSEA) revealed a reduced pathway activation linked to the basal-like phenotype such as KRAS signaling in the post-FFX organoids. WES did not show major differences in the genetic landscape of the tumor pre- and post-FFX induction suggesting a plasticity process rather than a clonal selection during chemotherapy. 2D cells were subjected to an unbiased automated drug screening of 415 compounds to investigate FFX-induced vulnerabilities. Top targets such as MEK inhibitors were validated manually in the 2D cells and organoids and an increased sensitivity was observed in the post-FFX cells. Thus, integrating functional layers into personalized medicine allows to identify chemotherapy-induced vulnerabilities as potent targeted therapy options in PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193389 | GEO | 2022/03/09

REPOSITORIES: GEO

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Subtypes in human pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses

Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses. METHODS: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared. RESULTS: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were significantly more sensitive to simvastatin than poorly differentiated PDOs. CONCLUSIONS: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.

2021-08-07 | GSE181593 | GEO

Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution.

Project description:Our findings reveal a high degree of both genomic and transcriptomic heterogeneity in established and globally utilized PDAC cell lines, custodial variation induced by growing apparently identical PDAC cell lines in different laboratories, and profound transcriptomic shifts in transitioning from 2D to 3D spheroid growth models. Our findings also call into question the validity of widely available immortalized, non-transformed pancreatic lines as contemporaneous “control” lines in experiments. Further, while patient-derived organoids (PDOs) are known to reflect the cognate in vivo biology of the parental tumor, we identify transcriptomic shifts during ex vivo passage that might hamper their predictive abilities over time. The impact of these findings on rigor and reproducibility of experimental data generated using established preclinical PDAC models between and across laboratories is uncertain, but a matter of concern.

2022-04-28 | GSE173339 | GEO

Patient-derived organoids of pancreatic ductal adenocarcinoma for subtype determination and clinical outcome prediction

Project description:Two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the “Classical” and “Basal-like” subtypes. However, the “molecular” classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction. We constructed a PDO library for morphologic and RNA-seq analyses and drug response assays in vitro. PDOs of PDAC were established at a high efficiency (> 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) or densely proliferating inside (DP type). RNA-seq analysis revealed that the “morphological” subtype (GL vs. DP) roughly corresponded to the “molecular” subtype (“Classical” vs. “Basal-like”). The proposed “morphological” classification predicted clinical treatment response and prognosis; the median overall survival of patients with GL type were significantly longer than that of those with DP type (P < 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK and autophagy inhibition. PDAC PDOs facilitated subtype determination and clinical outcome prediction, thereby advancing precision medicine for PDAC.

2024-04-11 | GSE228801 | GEO

Culture media composition influences patient-derived organoids ability to predict therapeutic response in gastrointestinal cancers

Project description:In this study, we have generated patient-derived organoids (PDOs) from primary and metastatic lesions of gastrointestinal cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma and evaluated their ability to predict donor tumor drug response. Specifically, we examined individual PDO responses to therapeutic agents with the observed clinical responses of donor patients to the same treatments and demonstrated an approximately 80% concordance rate. Importantly, we found a profound influence of culture media in PDOs phenotypes, we observed a significant difference in response to common PDAC chemotherapies, distinct morphologies, and transcriptomes between media in the same PDOs. These studies demonstrate the important role of culture media when using PDOs to inform patient care and predict response across a spectrum of GI cancers. We compared transcriptome data from pancreatic ductal adenocarcinoma patient-derived organoids in two media (WNT and PaTOM).

2022-10-12 | GSE212014 | GEO

USP25 is a HIF-1 regulator and a therapeutic target in pancreatic ductal adenocarcinoma

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:CRC-PDOs for personalized chemotherapy

| PRJNA814344 | ENA

Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment

Project description:Single-cell RNA-seq analysis of primary and metastatic (liver) human PDAC tumors, some pre-treatment and some post-chemotherapy. (Please note that although the file has "RAW" in the name these are the filtered results from CellRanger.)

2023-01-09 | GSE205013 | GEO

Trellis Single-Cell Screening Reveals Stromal Regulation of Patient-Derived Organoid Drug Responses

Project description:Patient-derived organoids (PDOs) can model personalized therapy responses, however current screening technologies cannot reveal drug response mechanisms or how tumor microenvironment cells alter therapeutic performance. To address this, we developed a highly-multiplexed mass cytometry platform to measure post translational modification (PTM) signaling, DNA-damage, cell-cycle activity, and apoptosis in >2,500 colorectal cancer (CRC) PDOs and cancer associated fibroblasts (CAFs) in response to clinical therapies at single-cell resolution. To compare patient- and microenvironment specific drug responses in thousands of single-cell datasets, we developed Trellis — a highly-scalable, hierarchical tree-based treatment effect analysis method. Trellis single-cell screening revealed that on-target cell-cycle blockage and DNA-damage drug effects are common, even in chemorefractory PDOs. However, drug-induced apoptosis is rare, patient-specific, and aligns with cancer cell PTM signaling. We find that CAFs can regulate cancer cell plasticity — shifting proliferative stem cells to slow-cycling revival stem cells via YAP to protect cancer cells from chemotherapy.

2023-12-06 | GSE239386 | GEO

SOAT1 knock-out downregulates the expression of mevalonate pathway genes in PDAC organoids

Project description:One of the emerging cancer vulnerabilities is altered metabolism, and several metabolic pathways have been shown to promote pancreatic ductal adenocarcinoma (PDAC). Here we use genetic targeting to delete SOAT1 from murine PDAC metastasis organoids, and use RNA-seq to identify genes differentially regulated in normal and cholesterol-supplemented media conditions in the presence or absence of SOAT1.

2020-06-16 | GSE141737 | GEO

The epigenetic landscape of human colorectal cancer

Project description:We characterized the epigenetic landscape of human colorectal cancer (CRC). To this extent, we performed gene expression profiling using high throughput sequencing (RNA-seq) and genome wide binding/occupancy profiling (ChIP-seq) for histone modifications correlated to transcriptional activity, enhancers, elongation and repression (H3K4me3, H3K4me1, H3K27Ac, H3K36me3, H3K27me3) in patient-derived organoids (PDOs), and in normal and tumoral primary colon tissues. We also generated ChIP-seq data for transcription factors YAP/TAZ in human CRC PDOs.

2021-02-23 | E-MTAB-8416 | biostudies-arrayexpress

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