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Bulk RNA-seq analysis of Human ASCP and ACC Pancreas Tumors

ABSTRACT: Identifying the cells from which cancers arise, and the paths they take towards malignancy is critical for understanding the molecular basis of tumor initiation and progression. To determine whether stem and progenitor cells can serve as cells of origin for cancer, we created a new Msi2-CreERT2 knock-in strain. When crossed to a conditional CAG-LSL-MycT58A model, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma of the pancreas (ASCP), acinar cell carcinoma (ACC), and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that oncogenic MYC preferentially triggers the transformation of the most immature subset of Msi2+ cells, leading to the rise of a common pool of pre-cancer cells with multi-lineage properties. These pre-cancer cells subsequently diverge to distinct pancreatic cancer subtypes by activation of distinct transcriptional programs and large-scale genomic changes. Importantly, the enforced expression of specific molecular signals can redirect cells toward specific subtypes. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of Msi2+ cells and provides a powerful framework to understand and control the programs that shape divergent fates in pancreatic cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241226 | GEO | 2023/08/21

REPOSITORIES: GEO

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scRNA-seq analysis of Musashi2-CreER-MycT58A; R26-LSL-tdTomato Mouse pre-cancer derived Pancreas ASCP, PDAC, and ACC Tumors (post transplantation)

Project description:Identifying the cells from which cancers arise, and the paths they take towards malignancy is critical for understanding the molecular basis of tumor initiation and progression. To determine whether stem and progenitor cells can serve as cells of origin for cancer, we created a new Msi2-CreERT2 knock-in strain. When crossed to a conditional CAG-LSL-MycT58A model, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: pancreatic ductal adenocarcinoma (PDAC), adenosquamous carcinoma of the pancreas (ASCP), acinar cell carcinoma (ACC), and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that oncogenic MYC preferentially triggers the transformation of the most immature subset of Msi2+ cells, leading to the rise of a common pool of pre-cancer cells with multi-lineage properties. These pre-cancer cells subsequently diverge to distinct pancreatic cancer subtypes by activation of distinct transcriptional programs and large-scale genomic changes. Importantly, the enforced expression of specific molecular signals can redirect cells toward specific subtypes. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of Msi2+ cells and provides a powerful framework to understand and control the programs that shape divergent fates in pancreatic cancer.

2023-08-22 | GSE241231 | GEO

scATAC-seq analysis of Msi2CreER-MycT58A Mouse Pre-cancer and Pancreas ASCP tumor

Project description:scATAC-seq analysis evaluating epigenetic heterogeneity in mouse pre-cancer and pancreas ASCP tumor

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Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [ATAC-seq]

Project description:We applied DNA content flow cytometry to a series of adenosquamous cancer of the pancreas (ASCP) tumor samples and patient derived xenografts (PDXs). We interrogated purified sorted tumor fractions from each sample with whole genome copy number variant (CNV) and whole exome sequencing (WES) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well characterized genomic lesions including mutations in KRAS and TP53, homozygous deletion of CDKN2A, and amplification of c-MYC, that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of ASCP and pancreatic ductal adenocarcinoma (PDAC) genomes using flow sorted PDX models distinguished genes with accessible chromatin in ASCP genomes including the lysine methyltransferase SMYD2, the pancreatic cancer stem cell driver RORγ, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes. Organoids derived from these models were used to screen compounds of interest. Notably a FGFR inhibitor had significant activity against the FGFR1-ERLIN2 fusion positive PDX.

2020-01-14 | GSE143563 | GEO

Genomic Landscape and Therapeutic Targets of Adenosquamous Carcinoma of the Pancreas [CGH Microarray]

2020-01-08 | GSE143256 | GEO

Molecular subtypes in pancreatic adenocarcinoma [pancreatic cancer cell lines]

Project description:The goal of the study was to examine the transcriptional profile of pancreatic cancer cell lines and assess if the molecular subtypes observed in tumor samples were represented in existing cell line models. Cell line models allow us to investigate if the molecular subtype observed in tumor have unique sensitivity profiles to anticancer drugs. 29 pancreatic cancer cell lines were compared to a mixed reference pool of 30 pancreatic cancer cell lines to identify cell line specific gene expression.

2016-06-01 | E-GEOD-77850 | biostudies-arrayexpress

Single Cell RNA seq of Genetically Engineered Mouse Models of Pancreatic Adenocarcinoma

Project description:We report the scRNAseq profiles of three mouse models of pancreatic cancer: KIC, KPfC, KPC. Analyses demonstrate the existence of 2 molecular subtypes of cancer cells, 2 molecular subtypes of cancer associated fibroblasts, and 2 molecular subtypes of cancer associated macrophages.

2019-01-25 | GSE125588 | GEO

Homo sapiens

Project description:Molecular subtypes in pancreatic adenocarcinoma [pancreatic cancer cell lines]

| PRJNA311744 | ENA

MUSASHI-2 RNA binding protein confers resistance to an epidermal growth factor receptor-tyrosine kinase inhibitor Osimertinib in lung adenocarcinoma

Project description:Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the acquired resistance to EGFR-TKIs, even third generation Osimertinib, the patients suffer poor prognosis. The resistance mechanisms are still not fully understood. Here, we demonstrate that increased expression of MUSASHI-2 (MSI2), an RNA binding protein, is novel mechanisms for resistance to EGFR-TKIs. We found that after long-exposure of gefitinib, the first generation EGFR-TKI, lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to not only gefitinib but also Osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the top list of the stemness-related genes upregulated in the EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including expression levels of Nanog a core stemness factor. We demonstrate that knockdown of MSI2 restored sensitivity to Osimertinib or gefitinib in the EGFR-TKI-resistant cells to the similar levels of the parental cells in vitro. RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to Osimertinib or gefitinib in parental cells. Finally, knockdown of MSI2 greatly increased sensitivity to Osimertinib in vivo. Collectively, our findings provide proof-of-principle that targeting MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent emergence of acquired resistance.

2021-08-27 | GSE168280 | GEO

RNA-seq of sorted pancreatic endocrine progenitor cells

Project description:Pancreatic endocrine cells arise from a NGN3+ population during pancreas organogenesis. To gain a more thorough understanding of this progenitor pool, we used a reporter mouse - NGN3-EGFP - and sorted EGFP+ cells from e15.5 pancreata of control animals. The data generated from this experiment will allow us to visualize gene expression levels in endocrine progenitors during normal development and can be used to compare against mutant animal gene expression.

2021-03-15 | GSE149889 | GEO

Mtor knockout in PDAC cells

Project description:A pancreatic ductal adenocarcinoma cell line was isolated from a Pdx1-Flp, FSF-KRasG12D/+, Rosa26-CreERT2/tdEG, Mtor-lox/lox mouse. Cultured cells were treated with 4-Hydroxytamoxifen to induce CreERT2 mediated excision of floxed Exon 3 of Mtor.

2017-10-16 | GSE98860 | GEO

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