Regulatory T cell depletion promotes oncogenic Kras driven pancreatic tumorigenesis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE120395 | GEO | 2019/09/24
REPOSITORIES: GEO
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Project description:Regulatory T cells (Treg) are common in the tumor microenvironment in both human pancreatic cancer and in genetically engineered mouse models of the disease. Previous studies in orthotopic syngeneic models of pancreatic cancer -recapitulated in our own data- indicated that Treg depletion results CD8+ T cell-mediated tumor regression. In human patients and in mouse models, regulatory T cells accumulate during the onset of Pancreatic Intraepithelial Neoplasia (PanIN), the earliest steps of carcinogenesis. We thus generated a genetic model to investigate the role of regulatory T cells during the onset of pancreatic carcinogenesis. Unexpectedly, depletion of Tregs during early stages of carcinogenesis led to accelerated tumor progression.
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Project description:Purpose: To study the expression and function of a novel cell cycle regulatory protein, human ecdysoneless (Ecd), during pancreatic cancer (PC) pathogenesis. Experimental Design: Immunohistochemical expression profiling of Ecd was done in non-neoplastic normal pancreatic tissues and pancreatic ductal adenocarcinoma lesions (from tissue microarray and Rapid Autopsy program) as well as precancerous PanIN lesions and metastatic organs. To analyze the biological significance of Ecd in PC progression, Ecd was stably knocked down in PC cell line followed by in vitro and in vivo functional assays. Results: Normal pancreatic ducts show very weak to no Ecd expression compared to significant positive expression in PC tissues (mean±SE composite score: 0.3±0.2 and 3.8±0.2 respectively, p<0.0001) as well as in PanIN precursor lesions with a progressive increase in Ecd expression with increasing dysplasia (PanIN-1 to PanIN-3). Analysis of matched primary tumors and metastases from PC patients revealed that Ecd is highly expressed in both primary pancreatic tumor and in distant metastatic sites. Further, knockdown of Ecd suppressed cell proliferation in vitro and tumorigenicity of PC cells in mice orthotopic tumors. Microarray study revealed that Ecd regulates expression of glucose transporter GLUT4 in PC cells and was subsequently shown to modulate glucose uptake, lactate production and ATP generation by PC cells. Finally, knockdown of Ecd also reduced level of pAkt, key signaling molecule known to regulate aerobic glycolysis in cancer cells. Conclusion: Ecd is a novel tumor promoting factor that is differentially expressed in pancreatic cancer and potentially regulates glucose metabolism within cancer cells.
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