Undefined
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB61243 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11216700_1.fastq.gz | Fastqsanger.gz | |||
| ERR11216700_2.fastq.gz | Fastqsanger.gz | |||
| ERR11216800_1.fastq.gz | Fastqsanger.gz | |||
| ERR11216800_2.fastq.gz | Fastqsanger.gz | |||
| ERR11217200.fastq.gz | Fastqsanger.gz |
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Project description:Multi-omics analysis of PARPi-naive and resistant KB1P(M) tumors
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Project description:Multi-omics analysis of PARPi-naive and resistant KB1P tumors-functional screening
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Project description:The aim of the study is to identify differences in the global phosphoproteome across a BRCA1-deficient mouse mammary tumor panel. We have matched PARPi-naive and PARPi-resistant tumors, in which resistance was induced in vivo (mice bearing tumors were treated with PARPi untill the tumors stopped responding). Each pair of matched naive/resistant tumors originate from a different original tumor donor (one can consider each individual donor as an individual patient). From another analysis (RAD51 IRIF) we know that the mechanism of PARPi-resistance in a number of the tumors is driven by alterations in DNA damage response. Therefore, we can divide the tumors into four groups: (A) HR proficient, the exact mechanism not known, (B) HR proficient due to the loss of 53bp1 (TP53BP1), (C) HR proficient due to loss of Rev7 (MAD2L2) and (D) HR deficient, mechanism of resistance not known. Additionally, each tumor from our panel was retransplanted and challenged with 15 Gy irradiation to trigger a DNA damage response, therefore for each tumor we have an irradiated (IR) and a non-irradiated (NIR) sample. In this experiment each sample was processed in duplicate. Given all this, group (A) consists of 6 individual donors x 2 (matched naive/resistant) x 2 (NIR/IR) x 2 (duplicate) = 48 samples (samples 1-48); groups (B)-(D): 2 donors (per group) x 2 (naive/resistant) x 2 (NIR/IR) x 2 (duplicate) = 16 samples/group (B: samples 65-80, C: samples 81-96 and D: 49-64, according to the OPL label). In total this gives: 48 + 16 +16 +16 = 96 samples. Part of this analysis is used in the paper that also describes data from PXD031711
2022-06-06 | PXD032007 | Pride
Project description:We have previously established an in vitro model of PARPi-resistant ovarian cancer by long-term exposure of UWB1.289 ovarian cancer cells (and their isogenic derivatives UWB1.289+BRCA1) to incrementally ascending olaparib concentrations. After finalizing this model, we performed RNA-seq, in order to identify differentially expressed transcript in the PARPi-resistant cells, with a focus on genes related to DNA-repair, multi-drug resistance and EMT. As a result, we show that the phenotype of PARPi resistance is associated with EMT-like traits and up-regulation of selective multi-drug related transcripts.
2023-07-31 | GSE235980 | GEO
Project description:Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient thus requiring the development of combination therapies that can capitalize on PARPi activity. We thus explored mechanisms underlying sensitivity and resistance to PARPi using two intrinsically sensitive and resistant syngeneic murine breast cancer models. Our data indicate that the PARPi sensitive tumor model has a high ratio of M1 anti-tumor/M2 pro-tumor macrophages with the M1/M2 ratio being increased by PARPi. In contrast the PARPi resistant tumor model had very low levels of M1 macrophages and thus a low M1/M2 ratio that was not altered by PARPi. Our data indicate that co-transplantation of the PARPi sensitive and the PARPi resistant tumor results in accumulation of M2 macrophages in the sensitive tumor, rendering the sensitive tumor PARPi resistant. C5aR1 and RPS19/C5aR1 signaling is selectively elevated in the M2 macrophages that are associated with PARPi resistance. Strikingly C5aR1 targeting decreased M2 macrophages, while sparing M1 macrophages rendering PARPi resistant tumors sensitive to PARPi. Consistent with the murine data, human breast cancers with high C5aR1 levels have a poor response to immune checkpoint blockade. Thus targeting C5aR1 may represent a therapeutic approach to selectively deplete M2 macropahges and engender sensitivity to PARPi and potentially other therapeutic approaches.
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Project description:Multi-omics analysis of ALT-positive neuroblastoma tumors
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Project description:PARP inhibitor (PARPi)-resistant BRCA mutant (BRCAm) high-grade serous ovarian cancer (HGSOC) represents a new clinical challenge with unmet therapeutic needs. Quantitative high-throughput drug combination screen identifies that ATR inhibitor (ATRi) and AKT inhibitor (AKTi) combination is a rational treatment strategy for both PARPi-sensitive and PARPi-resistant BRCAm HGSOC by inducing DNA damage and R-loop-mediated replication stress (RS). Mechanistically, the kinase domain of AKT1 directly interacts with DHX9, thus facilitating recruitment of DHX9 to R-loops. AKTi increases ATRi-induced R-loop-mediated RS by mitigating recruitment of DHX9 to R-loops. Moreover, DHX9 is upregulated in tumors from PARPi-resistant BRCAm HGSOC patients and high co-expression of DHX9 and AKT1 correlates with worse survival. Our study reveals a previously unknown interaction between AKT1 and DHX9 in R-loop resolution and novel mechanisms of action of AKTi and ATRi combination. Our data also provide a rationale for the clinical development of ATRi and AKTi combination for BRCAm HGSOC irrespective of PARPi resistance status and a potential biomarker to predict the response of combination therapy.
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Project description:94 sample with multi-omics analysis of ALT-positive neuroblastoma tumors, rna sequencing
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Project description:Background: PARP inhibitors (PARPi) kill cancer cells by stalling DNA replication and preventing DNA repair, resulting in a critical accumulation of DNA damage. Resistance to PARPi is a growing clinical problem in the treatment of high grade serous ovarian carcinoma (HGSOC). Acetylation of histone H3 lysine 14 (H3K14ac) and associated histone acetyltransferases (HATs) have known functions in DNA repair and replication, but their expression and activities have not been examined in the context of PARPi-resistant HGSOC. Results: Using mass spectrometry profiling of histone modifications, we observed altered H3K14ac enrichment in PARPi-resistant HGSOC cells relative to isogenic PARPi-sensitive lines. By RT-qPCR and RNA-Seq, we also observed altered expression of numerous HATs in PARPi-resistant HGSOC cells and a PARPi-resistant PDX model. Knockdown of HATs only modestly altered PARPi response, although knockdown and inhibition of PCAF significantly increased resistance. Pharmacologic inhibition of HBO1 severely depleted H3K14ac but did not affect PARPi response. However, knockdown and inhibition of BRPF3, which is known to interact in a complex with HBO1, did reduce PARPi resistance. Conclusions: This study demonstrates that severe depletion of H3K14ac does not affect PARPi response in HGSOC. Our data suggest that bromodomain functions of HAT proteins such as PCAF, or accessory proteins such as BRPF3, may play a greater role in PARPi response than acetyltransferase functions.
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Project description:Whole Genome sequencing of Multi-drug resistant Enterobacteriaceae from Healthy Children
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