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Gene expression profile at single cell level of an orthotopic mouse model with ZEB1 knockdown in the KPC cell line and control group mouse [spatial transcriptomic]

ABSTRACT: Pancreatic cancer is characterized by high resistance to chemotherapy and immunotherapy and there are no effective drugs which leads to poor overall survival for pancreatic cancer patients. The transcription factor ZEB1 promotes cellular plasticity and tumor metastasis in pancreatic cancer. We employed single-cell RNA sequencing and spatial transcriptomic sequencing to analyze ZEB1-mediated remodeling of the tumor microenvironment in pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE281083 | GEO | 2025/08/20

REPOSITORIES: GEO

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Gene expression profile at single cell level of an orthotopic mouse model with ZEB1 knockdown in the KPC cell line and control group mouse [scRNA-seq]

Project description:Pancreatic cancer is characterized by high resistance to chemotherapy and immunotherapy and there are no effective drugs which leads to poor overall survival for pancreatic cancer patients. The transcription factor ZEB1 promotes cellular plasticity and tumor metastasis in pancreatic cancer. We employed single-cell RNA sequencing and spatial transcriptomic sequencing to analyze ZEB1-mediated remodeling of the tumor microenvironment in pancreatic cancer.

2025-08-20 | GSE281084 | GEO

Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

Project description:Tumor-associated macrophages (TAMs) dynamically influence anti-tumor immunity. Understanding TAM function and plasticity is therefore critical to design immunotherapies. By combining syngeneic models of colorectal and pancreatic cancer with cell type-specific deletion of Zeb1, a key driver of epithelial-to-mesenchymal transition that is expressed in subsets of TAMs, we discovered that ZEB1 is an intrinsic regulator of TAM-controlled T cell trafficking. ZEB1 supports secretion of a subset of chemokines via the constitutive pathway, including CCL2 and CCL22, by promoting their biosynthesis, vesicular transport and release. This elevates CCL2 and CCL22-driven cytotoxic T cell (CTL) recruitment in vitro and fosters immunosurveillance by CTLs in tumors and metastases as well in an organotypic model for adoptive cell transfer. Our study identifies ZEB1 in TAMs as a facilitator of anti-tumor immunity, suggests a window of opportunity for cytokine-guided CTL tropism and reinforces the importance of onco-immunological context, particularly in the design of macrophage-/ cytokine-depleting strategies.

2025-05-07 | GSE286348 | GEO

ZEB1, a novel Junctional Adhesion Molecule A regulator, impacts sensitivity of pancreatic cancer-associated fibroblasts to oncolytic reovirus

Project description:Oncolytic virus (OV) therapy is a promising treatment for various tumors. However, in pancreatic ductal adenocarcinoma (PDAC), the high abundance of cancer-associated fibroblasts (CAFs) can limit OV therapy efficacy by impairing viral spread and anti-tumor immunity. We have previously shown that oncolytic reovirus infection of CAFs depends on expression of the reovirus entry receptor Junctional Adhesion Molecule A (JAM-A), which is not or lowly expressed in most PDAC CAFs. We propose that increasing the JAM-A expression on CAFs will boost viral spread in a tumor. However, there are currently no known regulators of JAM-A expression. Therefore, we performed a genome-wide CRISPR/Cas9 knock-out screen to identify regulators of JAM-A expression. Ablation of the top negative regulator, Zinc Finger E-Box binding Homeobox 1 (ZEB1), in pancreatic fibroblasts led to strong JAM-A upregulation. We show that ZEB1 directly regulates JAM-A expression by binding to the E-box regions located within the JAM-A promotor. Importantly, ZEB1 ablation increased the sensitivity of fibroblasts to reovirus infection and subsequent cell death. This paper provides a novel overview of genes regulating JAM-A expression and provides a rational approach of combining ZEB1 inhibition with reovirus therapy to target both CAFs and tumor cells in stroma-rich tumors like PDAC.

2025-10-29 | GSE290358 | GEO

Gene expression analysis of Panc1 pancreatic cancer cells with shRNA mediated control (GFP) or ZEB1 knockdown

Project description:Epithelial-to-mesenchymal transition (EMT) is a fundamental process in development and disease. If aberrantly activated it is a trigger for tumour progression and metastasis (Thiery et al 2009 Cell). It is now known that EMT activation is also associated with the maintenance of stem-cell properties (Mani et al. 2008 Cell). Since Zinc-finger enhancer binding transcription factor 1 (ZEB1) is a crucial EMT activator, we analyzed the changes in the gene expression profile that accompany shRNA mediated loss of ZEB1 in Panc1 pancreatic cancer cells. Panc1 is a cell line that exhibits relatively high ZEB1 levels and changes to a more benign phenotype upon ZEB1 knock down (Wellner et al. 2009 Nature Cell Biology). Panc1 cells were stably transfected with control (GFP) or ZEB1 shRNA. Upon puromycin selection, single cell clones were picked and characterized. Cells from two control versus two ZEB1 knockdown clones were harvested, total RNA was isolated and processed to hybridization.

2016-06-15 | E-MTAB-3483 | biostudies-arrayexpress

Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer

Project description:Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated macrophage M2-like phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in patients with breast cancer. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor-macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.

2022-03-09 | GSE189779 | GEO

Differentially expressed genes in KPC Cxcr2 KO vs KPC mouse PDAC

Project description:Recently, Bailey et al (2016, Nature) defined four subtypes of pancreatic cancer that are associated with distinct histopathological characteristics and differential survival, namely, Squamous, Pancreatic Progenitor, Immunogenic, and ADEX (Aberrantly Differentiated Endocrine eXocrine). We set out to assess by RNASeq whether loss of CXCR2 was significantly associated with a specific PDAC subtype. Pancreatic tumors were harvested from KPC or KPC Cxcr2-/- mice at endpoint (n=5 v 5), RNA prepared, and RNASeq analysis carried out. Reads were analysed using the bcbio-nextgen framework (https://bcbio-nextgen.readthedocs.org/en/latest/). After quality control and adaptor trimming, reads were aligned to the mouse genome build (UCSC mouse mm10) using STAR. Counts for known genes were generated using the function featureCounts in the R/Bioconductor package \Rsubread\. The R/Bioconductor package edgeR was used to identify differentially expressed genes.

2018-03-31 | E-MTAB-4659 | biostudies-arrayexpress

ZEB1 transcription factor promotes immune escape in melanoma

Project description:The efficacy of immunotherapies in metastatic melanoma depends on a robust T cell infiltration. Consistently, defining cancer cell intrinsic mechanisms mediating T cell exclusion and immune resistance is crucial. The EMT inducing transcription factor ZEB1 is a major regulator of melanoma cell plasticity, driving resistance to MAPK targeted therapies. Here, by analyzing the immune infiltrates of a cohort of melanoma patients, we demonstrate that high ZEB1 expression in tumor cells is associated with a decrease in CD8+ T lymphocyte infiltration, independently of beta-catenin pathway activation. Moreover, gain- or loss-of-function experiments in melanoma mouse models show that ZEB1 regulates tumor growth by controlling CD8+ T cell recruitment, via its negative action on the production of T cell attracting chemokines, and that its targeting improves the efficacy of anti-PD1 immunotherapy. Overall, the major role of ZEB1 in preventing T cell infiltration suggests it may constitute a new target in metastatic melanoma.

2022-03-23 | GSE169203 | GEO

ZEB1-regulated inflammatory phenotype in breast cancer cells

Project description:This SuperSeries is composed of the SubSeries listed below. Zinc finger E-box binding protein 1 (ZEB1) and ZEB2 induce epithelial-mesenchymal transition (EMT) and cancer progression. However, little is known about global picture of transcriptional regulation by ZEB1 and ZEB2. Here we identified an inflammatory phenotype regulated by ZEB1 using chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) in basal type breast cancer cells, followed by gene set enrichment analysis (GSEA) of ZEB1-bound genes.

2017-06-16 | GSE89206 | GEO

Gene expression profile at single cell level of an orthotopic mouse model with ZEB1 knockdown in the KPC cell line and control group mouse [spatial transcriptomic]

Project description:Gene expression profile at single cell level of an orthotopic mouse model with ZEB1 knockdown in the KPC cell line and control group mouse [spatial transcriptomic]

| PRJNA1182246 | ENA

The EMT-activator Zeb1 is crucial for cellular plasticity and drives metastasis in pancreatic cancer

Project description:Depletion of Zeb1 in a KPC-model for pancreatic cancer affected strongly the formation of precursor lesions, tumour grading, invasion and notably metastasis during PDAC progression. In this context, EMT is important for metastasis, but there is variability and specificity (and not redundancy) in the role and function of different EMT-inducing transcription factors.

2017-03-16 | GSE87472 | GEO

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