KRAS On vs OFF mouse cell lines
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ABSTRACT:
PROVIDER: PRJEB49092 | ENA |
REPOSITORIES: ENA
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Project description:Fungal mycobiome drives IL33 secretion and type 2 immunity in pancreatic cancer
| PRJNA785869 | ENA
Project description:Fungal mycobiome drives IL33 secretion and type 2 immunity in pancreatic cancer
| PRJNA787243 | ENA
Project description:We report the RNAseq of mouse pancreatic cancer cell lines with Kras ON vs Kras OFF. TH2 and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as IL4, IL5 and IL13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment (TME) are unknown. Here, in pancreatic ductal adenocarcinoma (PDAC), we show that oncogenic KrasG12D (Kras*) increases the expression of IL33 in cancer cells, which upon secretion recruits and activates the TH2 and ILC2. Correspondingly, cancer cell-specific deletion of IL33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, we discovered that the cellular release of IL33 into the TME is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases survival. Consistent with these murine data, high IL33 expression is observed in approximately 20% of human PDAC, and expression is mainly restricted to cancer cells. These data expand our knowledge of the mechanisms driving PDAC tumor progression and identifies therapeutically targetable pathways involving intratumoral mycobiome-driven secretion of IL33.
2022-03-01 | GSE190468 | GEO
Project description:TH2 and innate lymphoid cells 2 (ILC2) can stimulate tumor growth by secreting pro-tumorigenic cytokines such as IL4, IL5 and IL13. However, the mechanisms by which type 2 immune cells traffic to the tumor microenvironment (TME) are unknown. Here, in pancreatic ductal adenocarcinoma (PDAC), we show that oncogenic KrasG12D (Kras*) increases the expression of IL33 in cancer cells, which upon secretion recruits and activates the TH2 and ILC2. Correspondingly, cancer cell-specific deletion of IL33 reduces TH2 and ILC2 recruitment and promotes tumor regression. Unexpectedly, we discovered that the cellular release of IL33 into the TME is dependent on the intratumoral fungal mycobiome. Genetic deletion of IL33 or anti-fungal treatment decreases TH2 and ILC2 infiltration and increases survival. Consistent with these murine data, high IL33 expression is observed in approximately 20% of human PDAC, and expression is mainly restricted to cancer cells. These data expand our knowledge of the mechanisms driving PDAC tumor progression and identifies therapeutically targetable pathways involving intratumoral mycobiome-driven secretion of IL33.
2022-03-01 | GSE190103 | GEO
Project description:Focal adhesion kinase (FAK) is required for the expression of pro-inflammatory genes that inhibit anti-tumour immunity. Here, we show a novel and crucial role for the dual-function cytokine IL33 in FAK-dependent immune evasion. Specifically, nuclear FAK is required for the expression of IL33, the chemokine Ccl5 and the soluble form of the IL33 receptor, sST2, which are required for evasion of CD8+ T-cell-mediated anti-tumour immunity. Mechanistically, nuclear IL33 associates with FAK and a network of chromatin modifiers and transcriptional regulators, including Taf9, WDR82 and BRD4, while sST2 likely negates effects of IL33 secreted into the tumour microenvironment by infiltrating host immune cells. Finally, protein interaction network analysis implies that nuclear FAK–IL33 complexes impact on transcription factors that regulate NFkB and chemokines like Ccl5 downstream. Our data therefore provide new mechanistic insight into how FAK controls the tumour immune environment via a FAK–IL33/sST2 pathway and demonstrate a novel role for nuclear IL33 downstream of FAK as a component of transcription regulatory complexes that critically modulate anti-tumour immunity.
2017-12-06 | PXD007698 | Pride
Project description:Aberrant type 1 immunity drives mucosal fungal infection susceptibility
| PRJNA552029 | ENA
Project description:Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.
2024-09-22 | GSE277392 | GEO
Project description:We investigated the genetic profiles of IL33 and PD1-treated group 2 innate lymphoid cells (ILC2) harvested from KPC tumors and draining lymph nodes in a pancreatic ductal adenocarcinoma (PDAC) mouse model.
2019-09-03 | GSE136720 | GEO
Project description:Invasive fungal pathogens are major causes of human mortality and morbidity1,2. While numerous secreted effector proteins that reprogram innate immunity to promote virulence have been identified in pathogenic bacteria, there are no examples of analogous secreted effector proteins produced by human fungal pathogens. Cryptococcus neoformans, the most common cause of fungal meningitis and a major AIDS pathogen, induces a pathogenic type 2 response characterized by pulmonary eosinophilia and alternatively activated macrophages3-8. Here, we identify Cpl1 as an effector protein secreted by C. neoformans that drives alternative activation (also known as M2 polarization) of macrophages to enable pulmonary infection. We observed that Cpl1-enhanced macrophage polarization requires Toll-like receptor 4, best known as a receptor for bacterial endotoxin, but is also a poorly understood mediator of allergen-induced type 2 responses9-12. We show that this effect is due to Cpl1 itself and not contamination by lipopolysaccharide. Cpl1 is essential for virulence, drives polarization of interstitial macrophages in vivo, and requires type 2 cytokine signaling for its impact on infectivity. Strikingly, C. neoformans selectively associates with polarized interstitial macrophages during infection, suggesting a mechanism by which C. neoformans generates its own intracellular replication niche within the host. This work identifies a novel circuit whereby a secreted effector protein produced by a human fungal pathogen reprograms innate immunity, revealing an unexpected role for Toll-like receptor 4 in pathogenesis of infectious disease.
2022-08-12 | GSE203483 | GEO