Single-cell RNAseq of from murine pancreas tumor (KPC)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE294749 | GEO | 2026/01/09
REPOSITORIES: GEO
Similar Datasets
Project description:Pancreatic cancer is a highly innervated gastrointestinal disease in which sympathetic nerves play a critical role in modulating tumor growth and the tumor microenvironment (TME). While recent studies suggest that sympathetic nerves influence various TME components, including lymphoid and myeloid immune cells, their interactions with cancer-associated fibroblasts (CAFs) remain poorly understood. CAFs are a hallmark of pancreatic tumors and are known to upregulate axon guidance and neuroactive cues, suggesting a potential feedback loop with tumor-innervating nerves. Here, we investigated the bidirectional crosstalk between sympathetic nerves and CAFs in human and mouse pancreatic tumors. Using a chemo-genetic ablation model, we selectively eliminated pancreatic sympathetic nerves and found that denervation significantly reduced tumor size in female mice. To further dissect this interaction, we established co-culture systems with immortalized pancreatic fibroblasts and primary sympathetic neuron explants, identifying key transcriptional changes driven by CAF-sympathetic nerve signaling. Our findings demonstrate that sympathetic signaling enhances CAF activation and extracellular matrix remodeling, while activated CAFs, in turn, induce transcriptional programs in sympathetic neurons associated with nerve injury response. These results establish CAFs as central mediators of the tumor-supportive role of sympathetic nerves, offering new insights into the neural regulation of pancreatic cancer progression.
2026-02-12 | GSE318481 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Treatment of a short-term explant culture of cancer-associated fibroblasts (CAFs) from a KPC-Brca1 mouse pancreatic carcinoma, with 2 micromolar 5-aza-dC (decitabine; DAC) for 48 hours. The experiment includes 3 replicate plates untreated and 3 replicates treated.
2013-01-01 | E-GEOD-42364 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy. Treatment of a short-term explant culture of malignant epithelial cells from a KPC-Brca1 mouse pancreatic carcinoma, with 0.5 micromolar 5-aza-dC (decitabine; DAC) for 48 hours. The experiment includes 3 replicate plates untreated and 3 replicates treated.
2013-01-01 | E-GEOD-42365 | biostudies-arrayexpress
Project description:In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) promotes fibrotic, therapy-resistant tumours. Conversely, suppression of CAFs can result in aggressive metastatic tumours. Here we show that the Rho-effector kinase protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 was associated with reduced PSC proliferation and contractility, retention of lipid droplets and decreased a-SMA stress fibres. PKN2 loss was also associated with a myofibroblast CAF to -like inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. In spheroid co-cultures with PDAC cells, loss of PKN2 prevented PSC invasion but, counter-intuitively, promoted invasive cancer cell outgrowth. Further, deletion of PKN2 in the pancreatic stroma induced more locally invasive, orthotopic pancreatic tumours. Finally, we demonstrated that a PKN2KO PKN2 KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast differentiation function can limit important stromal tumour suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.
2021-11-19 | GSE189027 | GEO
Project description:In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) promotes fibrotic, therapy-resistant tumours. Conversely, suppression of CAFs can result in aggressive metastatic tumours. Here we show that the Rho-effector kinase protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 was associated with reduced PSC proliferation and contractility, retention of lipid droplets and decreased a-SMA stress fibres. PKN2 loss was also associated with a myofibroblast CAF to -like inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. In spheroid co-cultures with PDAC cells, loss of PKN2 prevented PSC invasion but, counter-intuitively, promoted invasive cancer cell outgrowth. Further, deletion of PKN2 in the pancreatic stroma induced more locally invasive, orthotopic pancreatic tumours. Finally, we demonstrated that a PKN2KO PKN2 KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast differentiation function can limit important stromal tumour suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.
2021-11-22 | GSE189245 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
2013-01-01 | GSE42365 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that resists current treatments. To test epigenetic therapy against this cancer we used the DNA demethylating drug 5-aza-2’-deoxycytidine (DAC) in a KrasLSL-G12D; p53LSL-R270H/+; Pdx1-cre; Brca1flex2/flex2 (KPC-Brca1) mouse model of aggressive stroma-rich PDAC. In untreated tumors, we found globally decreased 5-methyl-cytosine (5mC) in malignant epithelial cells and in cancer-associated myofibroblasts (CAFs), and increased amounts of 5-hydroxymethyl-cytosine (5HmC) in CAFs, in progression from pancreatic intraepithelial neoplasia (PanIN) to PDAC. DAC further reduced DNA methylation and slowed PDAC progression, markedly extending survival in an early treatment protocol and significantly though transiently inhibiting tumor growth when initiated later, without adverse side effects. Escaping tumors contained areas of sarcomatoid transformation with disappearance of CAFs. Mixing-allografting experiments and proliferation indices showed that DAC efficacy was due to inhibition of both the malignant epithelial cells and the stromal CAFs. Expression profiling and immunohistochemistry highlighted DAC-induction of STAT1 in the tumors, and DAC plus gamma-interferon produced an additive anti-proliferative effect on PDAC cells. DAC induced strong expression of the testis antigen DAZL in CAFs. These data show that DAC is effective against PDAC in vivo and provide a rationale for future studies combining hypomethylating agents with cytokines and immunotherapy.
2013-01-01 | GSE42364 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer associated fibroblasts (CAFs). CAFs promote tumor growth, metastasis and treatment resistance. We aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAFs) were generated by continuous incubation in 100nM gemcitabine. Gene expression differences between treatment naïve CAFs (N-CAFs) and R-CAFs were compared by array analysis. Immortalized human pancreatic CAFs were grown for 30 days in either control media or media containing 100nM gemcitabine. RNA was then isolated and hybidized on U133 Plus 2.0 Affymetrix arrays.
2016-03-09 | E-GEOD-78982 | biostudies-arrayexpress
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:Lymph nodes (LNs) are peripheral immune organs innervated by sympathetic and sensory nerves. Upon diverse stimuli, LNs undergo substantial structural reorganization and volume expansion. However, the adaptation of innervation to these changes remains poorly understood. In this study, whole-mount 3D imaging revealed that sympathetic nerve fibers, rather than sensory nerves, exhibited significant elongation and increased branching over time during tumor-induced lymph node enlargement (TLNE). Single-nucleus RNA Sequencing (snRNA-seq) analysis demonstrated that throughout TLNE, fibroblastic reticular cells (FRCs) are activatedand engage in neuro-related signaling pathways while secreting substantial amounts of hepatocyte growth factor (HGF). Moreover, the stiffness of the extracellular matrix (ECM) in LNs increased in the context of TLNE, further supporting FRC activation and HGF secretion. The role of HGF in promoting sympathetic nerve fiber outgrowth was confirmed by administering specific HGF inhibitors or using adeno-associated virus (AAV)-mediated HGF silencing. Collectively, HGF secreted by FRCs plays a pivotal role in TLNE, triggering adaptive sympathetic nerve outgrowth and reinnervation within LNs, providing novel insights into neuro-stromal-immune system crosstalk.
2026-05-01 | GSE280461 | GEO