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Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion due to R-loop accumulation IV

ABSTRACT: Kras is the most commonly mutated oncogene in human cancer and mutant Kras is responsible for over 90% of pancreatic ductal adnocarcinoma (PDAC), the most leath cancer. Here, we identified that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult panreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin and therby abbarrent R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We also demonstrate that the sepcific demand for PAF1C by cancer cells is due to the global activation of enhancers and thus eRNA transcription during tumorigenesis. The work provides a novel insight in how transcription addiction is caused during tumorigenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE217744 | GEO | 2023/11/01

REPOSITORIES: GEO

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Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion due to R-loop accumulation III

Project description:Kras is the most commonly mutated oncogene in human cancer and mutant Kras is responsible for over 90% of pancreatic ductal adnocarcinoma (PDAC), the most leath cancer. Here, we identified that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult panreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin and therby abbarrent R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We also demonstrate that the sepcific demand for PAF1C by cancer cells is due to the global activation of enhancers and thus eRNA transcription during tumorigenesis. The work provides a novel insight in how transcription addiction is caused during tumorigenesis.

2023-11-01 | GSE217742 | GEO

Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion due to R-loop accumulation II

2023-11-01 | GSE217741 | GEO

Aberrant accumulation of Kras-dependent enhancer RNAs during tumor progression renders cancer cells susceptible to PAF1 depletion due to R-loop accumulation I

2023-11-01 | GSE217740 | GEO

The PAF1 complex promotes 3‘ processing of pervasive transcripts

Project description:The PAF1 complex (PAF1C) functions in multiple transcriptional processes involving RNA Polymerase II (Pol II). eRNAs and PROMPTs are pervasive transcripts transcribed by Pol II and rapidly degraded by the nuclear exosome complex after 3’ endonucleolytic cleavage by the Integrator complex (Integrator). Here we show that PAF1C has an unexpected role in the termination of eRNAs and PROMPTs that are cleaved 1-3 kb downstream of the transcription start site. Mechanistically, PAF1C facilitates recruitment of Integrator to sites of pervasive transcript cleavage, promoting timely cleavage and transcription termination. We also show that PAF1C recruits Integrator to coding genes, where PAF1C then dissociates from Integrator upon entry into processive elongation. Our results demonstrate an unexpected function for PAF1C in limiting the length and accumulation of pervasive transcripts that result from nonproductive transcription

2022-03-03 | PXD031531 | Pride

Pten deficiency cooperates with KrasG12D to activate NFkB pathway promoting the development of malignant pancreatic ductal adenocarcinoma

Project description:Almost all human pancreatic ductal adenocarcinomas (PDACs) are driven by oncogenic Kras and the progression of the disease is characterized by the serial appearance of certain genetic lesions. Mouse models have convincingly shown that Kras mutation induces classical PanIN lesions that can progress to PDAC in the appropriate tumor suppressor background. However, the cooperative mechanism between mutant Kras-dependent signaling surrogates and other oncogenic pathways remains to be fully elucidated in order to devise better therapeutic strategy. Mounting evidence PTEN/PI3K perturbation on PDAC tumorigenesis, we observed frequent PTEN inactivation at both genomic and histopathological levels in primary human PDAC samples. The importance of PTEN/PI3K pathway during the development of PDAC was further supported by genetic studies demonstrating that Pten deficiency in cooperation with Kras activation accelerated the formation of invasive PDAC. Mechanistically, combined Kras mutation and Pten inactivation leads to NFkB activation and subsequent induction of cytokine pathways, accompanied with strong stromal activation and immune cell infiltration. Therefore, PTEN/PI3K pathway dictates the activity of NFkB network and serves as a major surrogate during Kras-mediated pancreatic tumorigenesis. Primary pancreatic ductal epithelial cell cultures were established from 6 week old Pdx1-Cre;LSL-KrasG12D L/+ (n=3) or Pdx1-Cre;LSL-KrasG12D L/+;Pten L/+ (n=5) mice. Total RNA was collected from early passage cells.

2011-08-31 | E-GEOD-25828 | biostudies-arrayexpress

Pten deficiency cooperates with KrasG12D to activate NFkB pathway promoting the development of malignant pancreatic ductal adenocarcinoma

2011-09-01 | GSE25828 | GEO

Mutant Kras- and p16-Regulated NOX4 Activation Overcomes Metabolic Checkpoints in Development of Pancreatic Ductal Adenocarcinoma

Project description:That mutational activation of Kras and inactivation of p16 are two signature genetic alterations required for development of PDAC. To elucidate the downstream pathways activated by oncogenic Kras and inactivated p16 in human pancreatic tumorigenesis, we profiled gene expression in HPNE/Kras/shp16 and HPNE/Kras cells using cDNA microarray analysis.

2016-11-03 | GSE89422 | GEO

Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer

Project description:Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial anti-tumor activity followed by recurrence due to cancer cell intrinsic and immune mediated paracrine mechanisms. Here, we explored the potential role of cancer associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2/ERBB3 receptor tyrosine kinases as a mechanism by which KRAS* independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in upregulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/ERBB3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitor in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.

2023-09-22 | GSE240232 | GEO

Use of DNA-alkylating pyrrole-imidazole polyamides for anti-cancer drug sensitivity screening in PDAC

Project description:Activating mutations of the KRAS gene are found in >90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, direct pharmacological targeting of the activated KRAS protein has been challenging. We previously reported that KR12, a DNA-alkylating pyrrole-imidazole polyamide designed to recognize the KRAS G12D/V mutation, showed an anti-tumor effect in colorectal cancer. In this study, we evaluated the anti-tumor effect of KR12 in PDAC. We found that KR12 inhibited tumor growth in a spontaneous PDAC mouse model, although the anti-tumor activity appeared to be limited in a human PDAC xenograft model. We developed a pyrrole-imidazole polyamide screening process based on the hypothesis that genetic elements otherwise unaffected by KR12 could exert attenuating effects on KRAS-suppression-resistant PDAC. We identified RAD51 as a potential therapeutic target in human PDAC cells. A RAD51 inhibitor showed an inhibitory effect on cell growth and affected the cytotoxic activity of KR12 in PDAC cells. These data suggested that the simultaneous inhibition of RAD51 and mutant KRAS blockage would be an important therapeutic strategy for PDAC.

2023-04-25 | GSE208243 | GEO

Arid1a restrains Kras-dependent changes in acinar cell identity

Project description:Mutations in members of the SWI/SNF chromatin remodeling family are common events in human cancer, but the mechanisms whereby disruption of SWI/SNF components alters tumorigenesis remain poorly understood. To model the effect of loss of function mutations in the SWI/SNF subunit Arid1a in pancreatic ductal adenocarcinoma (PDAC) initiation, we directed shRNA triggered, inducible and reversible suppression of Arid1a to the pancreas of mice in the setting of oncogenic KrasG12D. Arid1a cooperates with Kras in the adult pancreas as postnatal silencing of Arid1a following sustained KrasG12D expression induces rapid and irreversible reprogramming of acinar cells into mucinous PDAC precursor lesions. In contrast, Arid1a silencing during embryogenesis, concurrent with KrasG12D activation, leads to retention of acinar cell fate. Together, our results demonstrate Arid1a as a critical modulator of Kras-dependent changes in acinar cell identity, and underscore an unanticipated influence of timing and genetic context on the effects of SWI/SNF complex alterations in epithelial tumorigenesis.

2018-07-03 | GSE114576 | GEO

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