Project description:Transcriptional profile of PANC1 cells with CRISPR/Cas9 mediated deletion of BAP1 We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genome stability and its loss confers sensitivity to radio- and platinum-based therapies.
Project description:Transcriptional profile of murine Bap1 null pancreatic cancer cell lines We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genome stability and its loss confers sensitivity to radio- and platinum-based therapies
Project description:We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genomic stability and its loss confers sensitivity to radio- and platinum-based therapies.
Project description:We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genomic stability and its loss confers sensitivity to radio- and platinum-based therapies.
Project description:Transcriptional profile of human pancreatic cancer cell lines trerated with JQ1 inhibitor. Loss-of-function mutations of KDM6A, an X chromosome encoded histone H3K27 demethylase, are frequent in a broad spectrum of epithelial and hematopoietic malignancies and contribute to oncogenesis with so far poorly characterized mechanisms. Pancreas specific ablation of Kdm6a in mice accelerated Kras-driven cell transformation and compromised survival in a gender specific manner. Female knockout animals were particularly vulnerable and developed aggressive squamous and quasi-mesenchymal tumors with metastatic potential, as opposed to males which developed adenocarcinomas and exhibited a better prognosis. Integration of gene expression studies coupled to ChIP-seq profiling of chromatin modifications demonstrated that loss of Kdm6a caused genome-wide remodeling of bivalent promoters and rewiring of enhancer chromatin to repress endodermal fate by activating c-MYC and TP63 dependent transcriptional programs favoring squamous and quasi-mesenchymal differentiation.