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Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation (RNA-seq)

ABSTRACT: A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans- differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63- dependent manner. These non cell-autonomous effects occur, at least in part, through TP63- mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE140482 | GEO | 2020/04/27

REPOSITORIES: GEO

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Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation (ChIP-seq)

Project description:A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans- differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63- dependent manner. These non cell-autonomous effects occur, at least in part, through TP63- mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

2020-04-27 | GSE140481 | GEO

TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (RNA-seq)

Project description:The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative trans-differentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔN isoform) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. In addition, we demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion and an accelerated growth of primary PDA tumors and metastases in vivo. Conversely, we provide evidence that squamous PDA remains addicted to TP63 to sustain the growth of primary tumors and metastases. Taken together, our study validates the functional significance of squamous trans-differentiation in PDA, and reveals TP63-based reprogramming of PDA cells as an experimental tool for investigating vulnerabilities linked to this cell fate transition.

2018-11-13 | GSE115462 | GEO

TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (ChIP-seq)

2018-11-13 | GSE115461 | GEO

TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma

2018-11-13 | GSE115463 | GEO

Transcription profiling of mouse cancer associated fibroblasts (CAFs) reveals are activation in incipient neoplasia to orchestrate tumor promoting inflammation in an NF-I?B-dependent manner.

Project description:Full title: Cancer Associated Fibroblasts are activated in incipient neoplasia to orchestrate tumor promoting inflammation in an NF-ÎºB-dependent manner. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin cancer, we found a pro-inflammatory gene signature in CAFs isolated from dysplastic skin. This signature was also evident in CAFs from skin as well as mammary and pancreatic tumors in mice, and in human cancer. Surprisingly, the inflammatory signature was already activated in CAFs isolated from the incipient hyperplastic stage in multistep tumorigenesis. CAFs from this pathway functioned to promote macrophage recruitment, neovascularization and tumor growth in vivo, activities abolished when NF-ÎºB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be âeducatedâ by carcinoma cells to express pro-inflammatory genes. Experiment Overall Design: We performed expression profiling analysis of dermal fibroblasts sorted from dysplastic skin tissue of K14-HPV16 mice, and from age matched non transgenic controls. This array analysis was repeated in triplicate. Amplified RNA was hybridized to the 430 2.0 Affymetrix mouse genome arrays.

2009-09-13 | E-GEOD-17817 | biostudies-arrayexpress

CAFs are activated in incipient neoplasia to orchestrate tumor promoting inflammation in an NF-κB-dependent manner.

Project description:Full title: Cancer Associated Fibroblasts are activated in incipient neoplasia to orchestrate tumor promoting inflammation in an NF-κB-dependent manner. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion. We demonstrate that CAFs also mediate tumor-enhancing inflammation. Using a mouse model of squamous skin cancer, we found a pro-inflammatory gene signature in CAFs isolated from dysplastic skin. This signature was also evident in CAFs from skin as well as mammary and pancreatic tumors in mice, and in human cancer. Surprisingly, the inflammatory signature was already activated in CAFs isolated from the incipient hyperplastic stage in multistep tumorigenesis. CAFs from this pathway functioned to promote macrophage recruitment, neovascularization and tumor growth in vivo, activities abolished when NF-κB signaling was inhibited. Additionally, we show that normal dermal fibroblasts can be “educated” by carcinoma cells to express pro-inflammatory genes.

2009-09-02 | GSE17817 | GEO

Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

Project description:Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation

| PRJNA589900 | ENA

Expression data from gemcitabine treated pancreatic CAFs

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 naÃ¯ve 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

TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma

Project description:TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma

| PRJNA475105 | ENA

ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer

Project description:<p>Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal-like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal-like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-methylnicotinamide, a known oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptome and metabolome characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.</p>

2024-04-02 | MTBLS9418 | MetaboLights

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