Characterization of Genomic Heterogeneity and Evolution in Pancreatic Ductal Adenocarcinoma of KPC and KPTC
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132235 | GEO | 2019/12/03
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis as early-stage asymptomaticity leads to late-stage diagnoses. Strategies to detect PDAC earlier or identify predisposed individuals are therefore paramount. Here we report results from genetically engineered mice (GEMMs) and PDAC patients that identify serum proteins associated with pancreatic intraepithelial neoplasms (PanINs) (the most common PDAC precursor) and early-stage PDAC. Initially we screened previously described PanIN-abundant GEMMs, harbouring Pdx1-Cre, Lox-STOP-Lox-KrasG12D/+ and floxed alleles of essential autophagy genes Atg7-/- or Atg5-/-. Serum from these mice was assessed by proteomics and hits compared to those identified in KrasG12D/+ Trp53R172H/+ Pdx1-Cre (KPC) mice (which closely recapitulate human disease) and early-stage (I-II) PDAC patients. Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) was elevated in all three screens, with complement C5, complement factors B and H, and CD14 increased in KPC mice and PDAC patients; all significantly increase co-ordinately in PDAC, with each elevating with disease stage. Serum levels of C5, CFH and CD14 together constitute a novel panel for identifying PanINs and early-stage PDAC with confidence, and when combined with additional screening could help increase survival from this significant disease.
2026-06-15 | PXD065698 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis as early-stage asymptomaticity leads to late-stage diagnoses. Strategies to detect PDAC earlier or identify predisposed individuals are therefore paramount. Here we report results from genetically engineered mice (GEMMs) and PDAC patients that identify serum proteins associated with pancreatic intraepithelial neoplasms (PanINs) (the most common PDAC precursor) and early-stage PDAC. Initially we screened previously described PanIN-abundant GEMMs, harbouring Pdx1-Cre, Lox-STOP-Lox-KrasG12D/+ and floxed alleles of essential autophagy genes Atg7-/- or Atg5-/-. Serum from these mice was assessed by proteomics and hits compared to those identified in KrasG12D/+ Trp53R172H/+ Pdx1-Cre (KPC) mice (which closely recapitulate human disease) and early-stage (I-II) PDAC patients. Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) was elevated in all three screens, with complement C5, complement factors B and H, and CD14 increased in KPC mice and PDAC patients; all significantly increase co-ordinately in PDAC, with each elevating with disease stage. Serum levels of C5, CFH and CD14 together constitute a novel panel for identifying PanINs and early-stage PDAC with confidence, and when combined with additional screening could help increase survival from this significant disease.
2026-06-15 | PXD065578 | Pride
Project description:Pancreatic ductal adenocarcinoma (PDAC) has poor prognosis as early-stage asymptomaticity leads to late-stage diagnoses. Strategies to detect PDAC earlier or identify predisposed individuals are therefore paramount. Here we report results from genetically engineered mice (GEMMs) and PDAC patients that identify serum proteins associated with pancreatic intraepithelial neoplasms (PanINs) (the most common PDAC precursor) and early-stage PDAC. Initially we screened previously described PanIN-abundant GEMMs, harbouring Pdx1-Cre, Lox-STOP-Lox-KrasG12D/+ and floxed alleles of essential autophagy genes Atg7-/- or Atg5-/-. Serum from these mice was assessed by proteomics and hits compared to those identified in KrasG12D/+ Trp53R172H/+ Pdx1-Cre (KPC) mice (which closely recapitulate human disease) and early-stage (I-II) PDAC patients. Inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) was elevated in all three screens, with complement C5, complement factors B and H, and CD14 increased in KPC mice and PDAC patients; all significantly increase co-ordinately in PDAC, with each elevating with disease stage. Serum levels of C5, CFH and CD14 together constitute a novel panel for identifying PanINs and early-stage PDAC with confidence, and when combined with additional screening could help increase survival from this significant disease.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. The diversity and composition of intra-tumoral microbiota are associated with PDAC outcomes, and modulating the tumor microbiota has the potential to influence tumor growth and host-immune response. Here, we explore whether intervention with butyrate-producing probiotic can limit PDAC progression. By analyzing TCGA (PAAD) dataset, we found that tumoral butyrate-producing microbiota links to better prognosis and less aggressive features of PDAC. Intervention with Clostridium butyricum or its metabolite butyrate triggered superoxidative stress and intracellular lipid accumulation, which enhanced ferroptosis susceptibility of PDAC. Our study reveals a novel antitumor mechanism of butyrate, and suggests the therapeutic potential of butyrate-producing probiotics in PDAC.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) portends a dire prognosis. Intra-tumoral heterogeneity and cellular plasticity have emerged as hallmarks of cancer, including PDAC. Yet, our understanding of the mechanisms underpinning cellular diversity in PDAC remains limited. Here, we investigate cellular heterogeneity of PDAC cancer cells across a range of in vitro and in vivo growth conditions using single-cell genomics. We find heterogeneity contracts significantly in 2D and 3D cell culture models but becomes restored upon orthotopic transplantation. Orthotopic transplants reproducibly acquire cell states identified in autochthonous PDAC tumors, including a basal state exhibiting co-expression and co-accessibility of epithelial and mesenchymal genes. Using linage-tracing combined with single-cell transcriptomics, we demonstrate basal cells display high plasticity in situ. This work defines the impact of cellular growth conditions on phenotypic diversity and uncovers a highly plastic cell state with the capacity to facilitate state transitions and promote intra-tumoral heterogeneity in PDAC.
2022-07-25 | GSE209599 | GEO
Project description:We sought to determine whether certain miRNAs could serve as a biomarker for the prognosis of pancreatic ductal adenocarcinoma (PDAC) and uncover the uncharacterized miRNAs function in the pancreatic carcinogenesis
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Project description:Aging is a critical yet understudied determinant in pancreatic ductal adenocarcinoma (PDAC). Despite a strong epidemiological association with age, conventional PDAC preclinical models fail to capture the histopathological and stromal complexities that emerge in older organisms. Using an age-relevant syngeneic orthotopic model, we demonstrate that organismal aging accelerates PDAC progression and metastasis. Through transcriptomic profiling, we identify a conserved extracellular matrix gene signature enriched in cancer-associated fibroblasts (CAFs) from aged tumors, consistent with an augmented fibrotic landscape that supports immunosuppression, metastatic tropism, and poor prognosis. To directly test the functional impact of stromal aging, we employed heterochronic co-implantation models, revealing that revitalizing the aged tumor stroma with young CAFs restores immune infiltration and attenuates metastasis in older hosts. Conversely, aged CAFs, while immunosuppressive, fail to enhance metastasis in young hosts, suggesting that a youthful microenvironment exerts dominant regulatory control over disease progression. These findings demonstrate that stromal age is a critical modulator of both immune exclusion and metastatic behavior in PDAC. Importantly, our work establishes a new conceptual framework for understanding how aging shapes the tumor microenvironment in PDAC and opens a fertile avenue of investigation into age-specific stromal regulation. Moreover, this work raises compelling questions about the underlying molecular mechanisms—questions now accessible through our model—and lays the foundation for future efforts to therapeutically target stromal aging in PDAC.
2026-01-12 | PXD068597 | Pride
Project description:Characterization of Genomic Heterogeneity and Evolution in Pancreatic Ductal Adenocarcinoma of KPC and KPTC
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Project description:Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers, but divergent outcomes are apparent between patients. To delineate the intertumor heterogeneity that contributes to this, we aimed to identify clinically distinct gene expression-based subgroups. From a cohort of 345 resected pancreatic cancer cases, 90 samples with confirmed diagnosis of PDAC and sufficient tumor content were available for gene expression analysis by RNA sequencing. Unsupervised classification was applied, and a classifier was constructed. Species-specific transcript analysis on matching patient-derived xenografts (PDX, N=14) allowed construction of tumor- and stroma-specific classifiers for use on PDX models and cell lines.
2020-01-25 | E-MTAB-6830 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer due to its rapid progression, marked potential for metastasis and the difficulty in diagnosis1-3. However, there are no effective liquid tests currently available for PDAC detection besides CA19-9. Here we introduce a noninvasive detection approach that employs machine learning plus untargeted and targeted serum lipidomics to establish an accurate method to detect PDAC.
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