Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Increased activity of protein kinase A, even without DNAJB1, is sufficient to cause Fibrolamellar hepatocellular carcinoma

ABSTRACT: Most fibrolamellar carcinoma (FLC) is driven by a fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA holoenzyme activity is controlled through a regulatory protein (R) that both inhibits and localizes catalytic activity. An excess of regulatory subunits ensures PRKACA activity is normally inhibited. In FLC patient tumors driven by DNAJB1::PRKACA we find an increase in the ratio of catalytic to regulatory units by mass spectrometry, biochemistry and immunofluorescence, with increased kinase in the nucleus. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes of primary human hepatocytes; these recapitulated most changes observed in FLC. This is consistent with the observation that FLC is found in patients missing a regulatory subunit or with a ATP1B1::PRKACA fusion. Thus, the DNAJB1 domain is not required for FLC. Instead, changes in PKA quantity and localization determine the FLC phenotype.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Soren Heissel

LAB HEAD: Sanford M. Simon

PROVIDER: PXD043816 | Pride | 2024-05-17

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	AQUA_v2_April_2020.pptx	Other
	MS205845QEHF_Solomon_Simon_RU108_Normal.raw	Raw
	MS205845QEHF_Solomon_Simon_RU108_Normal_b.raw	Raw
	MS205845QEHF_Solomon_Simon_RU108_Tumor.raw	Raw
	MS205845QEHF_Solomon_Simon_RU108_Tumor_b.raw	Raw

Items per page:

1 - 5 of 23

Similar Datasets

Increased activity of protein kinase A, even without DNAJB1, is sufficient to cause Fibrolamellar hepatocellular carcinoma

Project description:Most fibrolamellar carcinoma (FLC) is driven by a fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes of primary human hepatocytes; these recapitulated most changes observed in FLC. This is consistent with the observation that FLC is found in patients missing a regulatory subunit or with a ATP1B1::PRKACA fusion. Thus, the DNAJB1 domain is not required for FLC.

2024-05-17 | GSE237697 | GEO

DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming

Project description:Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults defined by fusion of the DNAJB1 heat shock protein and protein kinase A (PKA) catalytic subunit (DNAJB1-PRKACA). The resulting chimeric protein has increased kinase activity and is essential for FLC xenograft growth. However, the critical oncogenic pathways controlled by DNAJB1-PRKACA have not been defined. Here, we explored this question by studying patient-derived FLC models and engineered systems and analyzing patient samples. We show that the core function of DNAJB1-PRKACA is the direct phosphorylation and inactivation of the Salt-inducible kinases. This leads to deregulation of the CRTC2 co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and global increases in histone acetylation necessary for malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest opportunities for therapeutic targeting of CRTC2/p300 in FLC. Notably, these findings link this signature fusion oncoprotein of a rare cancer type to more common cancer gene alterations involving the STK11 tumor suppressor and GNAS oncogene, which also function via SIK suppression.

2024-09-08 | GSE266253 | GEO

CDK7 is a novel therapeutic vulnerability in Fibrolamellar cancer

Project description:To identify targets in Fibrolamellar cancer (FLC), we introduced the FLC driver gene mutation (DNAJB1-PRKACA) into HepG2 cells to engineer FLC cell lines. We then performed gene expression profiling analysis using data obtained from RNA-seq of 6 different cell samples from HepG2, H33 (FLC cell line) and H12 (FLC cell line)

2024-08-01 | GSE232374 | GEO

Effects of fibrolamellar carcinoma-associated DNAJB1-PRKACA in HEK293T cells

Project description:Fibrolamellar carcinoma (FLC) is a type of primary liver cancer that commonly arises in adolescents and young adults in a background of normal liver tissue and has an overall poor prognosis due to lack of effective chemotherapeutic agents. The DNAJB1-PRKACA gene fusion (DP) has been reported in the majority of FLC tumors, however its exact oncogenic mechanisms are unclear. Given the paucity of cellular models, in particular FLC tumor cell lines, we hypothesized that engineering the DP fusion gene in HEK293T cells will provide insight into the oncogenic mechanism of the fusion gene. We used CRISPR/Cas9 to engineer HEK293T clones expressing DP fusion gene (HEK-DP) and performed transcriptomic, proteomic, and mitochondrial studies to characterize this cellular model. Transcriptomic analysis of HEK-DP cells revealed a significant increase in LINC00473 expression similar to primary FLC samples. Proteomic analysis identified mitochondrial proteins as well as proteins in other subcellular compartments which interact with DP. HEK-DP cells demonstrated significant mitochondrial fission which suggests a role for DP in altering mitochondrial dynamics. Our results support the use of the HEK-DP cells as a novel model for elucidating the oncogenic mechanisms underlying DNAJB1-PRKACA-associated FLC pathogenesis and as a platform for high-throughput drug targeting of DNAJB1-PRKACA protein.

2022-04-05 | GSE161932 | GEO

Chemical, molecular, and single cell analysis reveal chondroitin sulfate proteoglycan aberrancy in fibrolamellar carcinoma

Project description:Fibrolamellar carcinoma (FLC) is an aggressive liver cancer that predominantly afflicts adolescents and young adults. Patients with FLC are characterized by a heterozygous deletion on chromosome 19 that creates an oncogenic gene fusion, DNAJB1-PRKACA. The extracellular environment of FLC tumors is poorly characterized and may contribute to cancer progression, metastasis, and/or drug resistance. To bridge this knowledge gap, we propose to assess pathways relevant to proteoglycans, a major component of the extracellular matrix. We leveraged single-cell ATAC-seq to analyze the diversity of VCAN accessibility across different cell types.

2022-05-20 | GSE202315 | GEO

Presentation of DNAJB1-PRKACA fusion neoantigens by different HLA class I alleles

Project description:Fibrolamellar carcinoma (FLC) is a liver tumor with a high mortality burden and few treatment options. A promising therapeutic vulnerability in this disease is its highly conserved driver mutation: a gene fusion between DNAJB1 and PRKACA, which is expressed in virtually all FLC tumors and could be an ideal neoantigen target for immunotherapy. In this study, we aimed to define endogenous CD8 T cell responses to this fusion in FLC patients and evaluate fusion-specific T cell receptors (TCRs) as candidates for novel cellular immunotherapies. Although fusion-specific T cells in FLC appear to be rare, we nevertheless defined an endogenous functional T cell response in an FLC patient.

2024-05-24 | PXD042316 | Pride

Multi-omic analysis of microRNA-mediated regulation reveals a proliferative axis involving miR-10b in fibrolamellar carcinoma

Project description:Fibrolamellar carcinoma (FLC) is an aggressive liver cancer with low survival rates and no standard-of-care. The vast majority of FLC patients carry a causative somatic mutation that leads to the gene fusion, DNAJB1-PRKACA. To work toward novel therapeutic strategies, it is important to understand the mechanisms underlying FLC etiology and progression. To that end, in this study, we analyzed a large sample cohort (52 patients) using multiple genome-scale assays to define genes subject primarily to post-transcriptional regulation by microRNAs. These studies revealed a candidate master microRNA regulator in FLC, miR-10b. Functional experiments in cells established from a patient-derived xenograft model revealed that miR-10b contributes to FLC cell metabolic health and proliferation.

2021-11-03 | GSE181922 | GEO

Single cell RNA-seq and TCR-seq of T cell responses against DNAJB1-PRKACA

Project description:The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma (FL-HCC), a lethal disease lacking specific therapies. Here, we report on the identification, characterization and first immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in FL-HCC. To characterize the T cell response against DNAJB1-PRKACA-derived HLA class I and HLA class II ligands, single cell RNA sequencing (scRNA-seq) and single cell TCR profiling from CD4+ and CD8+ T cells were performed using 10x Genomics single cell immune profiling.

2022-09-12 | GSE210337 | GEO

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma

Project description:Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long non-coding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo models of disease. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, an indicator of mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.

2023-05-27 | GSE233148 | GEO

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma

2024-01-19 | GSE253465 | GEO