Incorporation of human iPS cell-derived stroma creates a pancreatic cancer organoid with heterogeneous cancer-associated fibroblasts [AmpliSeq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE243647 | GEO | 2023/11/13
REPOSITORIES: GEO
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Project description:The aggressiveness of pancreatic ductal adenocarcinoma (PDAC) is affected by a tumor microenvironment (TME). In this study, to recapitulate PDAC TME ex vivo, we cocultured patient-derived PDAC cells with mesenchymal and vascular endothelial cells derived from human induced-pluripotent stem cells (hiPSCs) to create a fused pancreatic cancer organoid (FPCO) in air–liquid interface. FPCOs were further induced to resemble two distinct parts of a PDAC tissue. Owing to various types of cancer associated fibroblasts (CAFs) derived from hiPSCs, the TME consisted of abundant extracellular matrix proteins, which likely conferred strong drug resistance to PDAC cells in one type of FPCOs. Because of re-proliferation capacity of PDAC cells after anticancer drug treatment, the other FPCO is the first culture system for investigating PDAC recurrence. Introducing hiPSC technology, we have created, for the first time, the PDAC organoids representing the heterogeneity of PDAC tissue, a potential platform for screening anticancer drugs.
2023-11-13 | GSE243649 | GEO
Project description:Autotaxin (ATX), encoded by ENPP2, catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME). ATX is a clinical target in pancreatic ductal adenocarcinoma (PDAC), yet the pro-tumorigenic action of the ATX/LPA axis in PDAC remains unclear. PDAC is characterized by a highly fibrotic tumor microenvironment (TME) due to an abundance of cancer associated fibroblasts (CAFs), acting as a barrier to therapy and contributing to the poor survival of PDAC patients. The mechanism by which ATX inhibition influences CAFs and their secretome is still not fully characterized. To identified potential downstream mediators of ATX signaling, we performed RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors, IOA-289 and PF-8380. PF-8380 treatment resulted in a higher number of differentially expressed genes compared to IOA-289 treatment. IOA-289 treatment resulted in only four significantly differentially expressed genes (CTGF, PLIN2, HHIP, and AHNAK). However, only PLIN2, which was upregulated and CTGF, which was downregulated, overlapped between the two ATX inhibitors. As CTGF (connective tissue growth factor) is a pro-fibrotic and pro-tumorigenic factor, it suggests a key role for CAF-derived ATX in promoting autocrine and paracrine pro-tumorigenic signaling in PDAC.
2024-10-06 | E-MTAB-14494 | biostudies-arrayexpress
Project description:A major impediment to the effective treatment of patients with PDAC (Pancreatic Ductal Adenocarcinoma) is the molecular heterogeneity of the disease, which is reflected in an equally diverse pattern of clinical responses to therapy. We developed an efficient strategy in which PDAC samples from 17 consecutively patients were obtained by EUS-FNA or surgery, their cells maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. For these patients a clinical follow up was obtained. On the breathing tumors we studied the RNA expression profile by an Affymetrix approach. We observed a significant heterogeneity in their RNA expression profile, however, the transcriptome was able to discriminate patients with long- or short-time survival which correspond to moderately- or poorly-differentiated PDAC tumors respectively. Cells allowed us the possibility to analyze their relative sensitivity to several anticancer drugs in vitro by developing a chimiogram, like an antibiogram for microorganisms, with several anticancer drugs for obtaining an individual profile of drug sensitivity and as expected, the response was patient-dependent. Interestingly, using this approach, we also found that the transcriptome analysis could predict the sensitivity to some anticancer drugs of patients with a PDAC. In conclusion, using this approach, we found that the transcriptome analysis could predict the sensitivity to some anticancer drugs and the clinical outcome of patients with a PDAC. PDAC samples from 17 consecutively patients were obtained by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery. Consents of informed patients were collected, and the ethics review board of the three centers approved the study. All samples were anonymized and obtained in accordance with institutional review boards. EUS-FNA cells were maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. We characterized 17 PDAC-derived xenografts by duplicate. Total RNA was extracted and hybridized on Human Gene 2.0 (Genechip, Affymetrix) as described previously (Hamidi et al. JCI 122: 2092-2103, 2012).
2015-04-09 | E-GEOD-55513 | biostudies-arrayexpress
Project description:Nuclear Protein 1 (Nupr1) is a major actor of the cell stress response required for KrasG12D-driven formation of pancreatic intraepithelial neoplastic (PanINs) lesions in mice. We investigated the impact of Nupr1-depletion on the development and biology of murin pancreatic adenocarcinomas (PDAC) in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mice. We found that only one half of Nupr1-deficient mice developed PDAC. This is related to increased caspase 3 activity and low IER3 expression in Nupr1-deficient;KIC in the pancreas. Moreover, when Nupr1-deficient;KIC mice do develop PDAC, tumors present with impaired epithelial-to-mesenchymal transition (EMT). Transcriptoma analysis revealed that Nupr1-deficient and Nupr1wt;KIC PDACs presented enrichment of gene signatures of the human classical- and quasi-mesenchymal (QM)-PDAC respectively. Moreover, Nupr1-deficient;KIC PDACs shared with human classical-PDACs overexpression of Kras-activation genes. In addition, cells derived from Nupr1-deficient;KIC PDACs formed fewer microspheres in vitro compared to Nupr1wt;KIC cells, indicative of stemness impairment in the absence of Nupr1. Finally, we found that Nupr1-deficient;KIC cells were more sensitive to some anticancer drugs than their Nupr1wt counterpart. Hence, this study establishes the pivotal role of Nupr1 in PDAC progression after PanIN and in PDAC EMT in vivo, with an impact in PDAC cell stemness. As a consequence, according to absence or presence of Nupr1, KIC mice develop tumors that phenocopy human classical- or QM-PDAC, respectively, thus becoming attractive models for preclinical drug trials. We investigated the impact of the homozygous deletion of the Nupr1 gene on pancreatic adenocarcinoma development and biology in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mouse model.
2012-12-16 | E-GEOD-42322 | biostudies-arrayexpress
Project description:Aberrant activation of the ERK signaling pathway triggers a protective anticancer response characterized by stable growth arrest and activation of tumor suppressors called cellular senescence. Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that activate the ERK pathway. Pancreatic intraepithelial neoplasia of low degree display high levels of phospho-ERK consistent with senescence acting as a barrier for malignant transformation. However, advanced lesions downregulate phospho-ERK levels circumventing the senescence barrier. Restoring ERK hyperactivation in PDAC using an activated allele of the kinase RAF, leads to ERK-dependent growth arrest with senescence biomarkers. Phosphoproteomics analysis of ERK-dependent senescence in PDAC revealed a decrease in several nucleolar phosphoproteins suggesting that high levels of ERK lead to senescence via nucleolar stress. Consistent with this explanation, ERK-dependent senescent cells displayed intranucleolar foci containing RNA polymerase I. Combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response of PDAC cells. The drug cocktail FOLFIRINOX, currently the best treatment for PDAC, also triggered ERK hyperactivation and nucleolar stress characterized by nucleolar foci, solid amyloid aggregates and a decrease in 5.8S and 28S rRNAs. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.
2024-06-10 | PXD032257 | Pride
Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
2015-11-21 | E-GEOD-75233 | biostudies-arrayexpress
Project description:Identifying mechanisms underlying tumor growth and immune resistance is needed to treat pancreatic ductal adenocarcinoma (PDAC) effectively. The complexity of the tumor microenvironment (TME) suggests that the crosstalk between cells in the TME could drive drug resistance and relapse in PDAC. We have previously determined that vasoactive intestinal peptide (VIP) is overexpressed in PDAC and that VIP receptors expressed on T cells are a targetable pathway that sensitizes PDAC to anti-PD1 therapy. In this study, we show that pancreatic cancer cells engage in autocrine signaling of VIP through VIP-receptor 2 (VPAC2), and that high co-expression of VIP with VPAC2 leads to reduced relapse-free survival in PDAC patients. Mechanistically, we identified piwi-like RNA-mediated gene silencing2 (Piwil2) as a tumor-cell intrinsic protein downstream of VPAC2 that regulates cancer cell growth. In addition, we discovered TGFβ-1 as a potential tumor-extrinsic inhibitor of T cell function induced by VPAC2 signaling. In vivo, knock out and knockdown of VPAC2 on PDAC cells led to reduced tumor growth rate and increased sensitivity to anti-PD-1 therapy in various mouse models of PDAC that were T- cell dependent. Overall, these findings emphasize the implications of VIP/VPAC2 signaling in the PDAC tumor microenvironment and further support the rationale for developing VPAC2-specific antagonists.
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Project description:We generated novel patient derived xenograft (PDX) and cell line -derived xenograft models for pancreatic ductal adenocarcinoma (PDAC) which reflect different molecular subtypes. Pancreatic ductal adenocarcinoma is currently the tumor with the fourth highest mortality rate. Recently, subtypes of PDAC have been reported by Collisson et al (Nat. Med. 17(4) 2011. DOI: 10.1038/nm.2344). However current fetal calf serum (FCS) cultured cell lines do not accurately model these subtypes. We thus generated novel serum-free cell lines derived from primary patient xenografts. We here analyse the gene-expression profiles of the xenografts and the derived cell lines. We show that indeed three different subtypes can be separated in our models based on gene-expression data. Further, we identify upregulation of a drug-detoxification pathway specifically in xenografts and cell lines of one of the subtypes. These models and data will help to better understand inter-patient heterogeneity in PDAC and identify novel drug targets and diagnostic markers.
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Project description:Cisplatin is a broad-spectrum anticancer drug, which is estimated to be administered to 40-80% of patients undergoing chemotherapy. However, its clinical utility is often limited due to factors that include acquired resistance of cancer cells to cisplatin. Because cisplatin is currently evaluated as a prospective agent for combined chemotherapy of pancreatic ductal adenocarcinoma (PDAC), we have investigated mechanisms involved in the acquired resistance of PDAC cells to cisplatin using gene expression study of two different parental-resistant pairs of PDAC cell lines. We have developed cisplatin-resistant cell lines AsPC1-R and BxPC3-R from their parental PDAC cell lines AsPC1 and BxPC3, respectively, by culturing them in medium with step-wise increasing concentration of cisplatin. Parental and resistant pairs of PDAC cells were analyzed by whole-transcript gene expression analysis.
2015-11-30 | GSE73978 | GEO
Project description:A major impediment to the effective treatment of patients with PDAC (Pancreatic Ductal Adenocarcinoma) is the molecular heterogeneity of the disease, which is reflected in an equally diverse pattern of clinical responses to therapy. We developed an efficient strategy in which PDAC samples from 17 consecutively patients were obtained by EUS-FNA or surgery, their cells maintained as a primary culture and tumors as breathing tumors by xenografting in immunosuppressed mice. For these patients a clinical follow up was obtained. On the breathing tumors we studied the RNA expression profile by an Affymetrix approach. We observed a significant heterogeneity in their RNA expression profile, however, the transcriptome was able to discriminate patients with long- or short-time survival which correspond to moderately- or poorly-differentiated PDAC tumors respectively. Cells allowed us the possibility to analyze their relative sensitivity to several anticancer drugs in vitro by developing a chimiogram, like an antibiogram for microorganisms, with several anticancer drugs for obtaining an individual profile of drug sensitivity and as expected, the response was patient-dependent. Interestingly, using this approach, we also found that the transcriptome analysis could predict the sensitivity to some anticancer drugs of patients with a PDAC. In conclusion, using this approach, we found that the transcriptome analysis could predict the sensitivity to some anticancer drugs and the clinical outcome of patients with a PDAC.
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