Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells
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ABSTRACT:
PROVIDER: PRJNA1032567 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26537065_1.fastq.gz | Fastqsanger.gz | |||
| SRR26537065_2.fastq.gz | Fastqsanger.gz | |||
| SRR26537066_1.fastq.gz | Fastqsanger.gz | |||
| SRR26537066_2.fastq.gz | Fastqsanger.gz | |||
| SRR26537067_1.fastq.gz | Fastqsanger.gz |
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Project description:TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cell therapy might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are unable to control AML cell outgrowth in vitro and in vivo compared to TP53 wildtype cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.
2023-10-31 | GSE246335 | GEO
Project description:TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wildtype cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.
| S-SCDT-10_1038-S44321-024-00024-2 | biostudies-other
Project description:Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and remains deadly in patients with high-risk disease. Single chimeric antigen receptor T-cell therapies (CAR-T) for solid tumor have shown poor efficacy in clinical trials due, in part, to T cell exhaustion and uneven expression of target antigens in tumors. Here, we attempted to target Glypican-2(GPC2) and CD276(B7-H3), both highly but heterogeneously expressed on NB cell surface, to overcome these challenges in single CAR T- therapies. First, to identify optimal binders for CAR T- cell targeting each antigen, we made individual CAR constructs using multiple binders against these antigens and utilized a multimodal approach including simultaneous protein and transcriptome measurement at single cell level to characterize each individual CAR T- cell in a pooled strategy. Combined with cell expansion and cytotoxicity assays, we identified the most effective CAR construct for each target.
2022-03-18 | GSE181437 | GEO
Project description:Targeting the mevalonate pathway to overcome acquired anti-HER2 treatment resistance in breast cancer [RNA-seq]
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Project description:Simvastatin has been widely used for treatment of hypercholesterolemia due to its ability to inhibit HMG-CoA reductase, the rate limiting enzyme of de novo cholesterol synthesis via mevalonate pathway. Its inhibitory action causes also depletion of pathway intermediates, farnesyl pyrophosphate (FPP) and geranyl-geranyl pyrophosphate (GGPP), which are inevitable for proper targeting of small GTPases (e.g. Ras proteins) to their site of action. We profiled by array the gene expression of MIA PaCa-2 cells treated with simvastatin, FPP, GGPP and their combinations. The inhibitory effect of statins on GFP-K-Ras protein trafficking were partially prevented by addition of the mevalonate pathway intermediates. We conclude that the anticancer effect of simvastatin is to a large extent mediated through isoprenoid intermediates of the mevalonate pathway.
2018-03-31 | E-MTAB-3263 | biostudies-arrayexpress
Project description:Chimeric antigen receptor (CAR) T cell therapy is a promising immunotherapy against cancer. Although there is a growing interest in other cell types, a comparison of CAR immune effector cells in challenging solid tumor contexts is lacking. Here, we compare mouse and human NKG2D-CAR expressing T cells, NK cells and macrophages against glioblastoma, the most aggressive primary brain tumor. In vitro we show that T cell cancer killing is CAR-dependent, whereas intrinsic cytotoxicity overrules CAR-dependence for NK cells and CAR macrophages reduce glioma cells in co-culture assays. In orthotopic immunocompetent glioma mouse models, systemically administered CAR T cells demonstrate superior accumulation in the tumor and each immune cell type induces distinct changes in the tumor microenvironment. An otherwise low therapeutic efficacy is significantly enhanced by co-expression of pro-inflammatory cytokines in all CAR immune effector cells, underscoring the necessity for multifaceted cell engineering strategies to overcome the immunosuppressive solid tumor microenvironment.
2024-12-03 | GSE283049 | GEO
Project description:Despite effective strategies, therapy resistance in HER2+ breast cancer remains a challenge. While the Mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Using HER2+ breast cancer parental (P) cell models (AU565, SKBR3, and UACC812), we have established anti-HER2-resistant derivatives made resistant to lapatinib (LR) or lapatinib plus trastuzumab (LTR). We performed RNA-seq on these resistant models and the P cells treated with lapatinib or lapatinib plus trastuzumaba for 24 h. We found that the average expression of the key genes in the MVA pathway, as a surrogate for pathway activity, was dramatically reduced in P cells with short-term treatment. In contrast, expression was restored or further upregulated relative to P cells in all three resistant (LR/LTR) models. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the n-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of resistant cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), but not by cholesterol. Activated YAP/TAZ and mTORC1 signaling and their downstream target gene product Survivin were inhibited by MVA blockade especially in the LR/LTR models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated S6 levels despite blockade of the MVA. The MVA may provide alternative signaling leading to cell survival and resistance when HER2 is blocked by activating YAP/TAZ-mTORC1-Survivin signaling suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy and warrant further clinical investigation.
2020-04-04 | GSE132055 | GEO
Project description:Isoprenoids are a class of ubiquitous organic molecules synthesized from the five-carbon starter unit isopentenyl pyrophosphate (IPP). Comprising more than 30,000 known natural products, isoprenoids serve various important biological functions in many organisms. In bacteria, undecaprenyl pyrophosphate is absolutely required for the formation of cell wall peptidoglycan and other cell surface structures, while ubiquinones and menaquinones, both containing an essential prenyl moiety, are key electron carriers in respiratory energy generation. There is scant knowledge on the nature and regulation of bacterial isoprenoid pathways. In order to explore the cellular responses to perturbations in the mevalonate pathway, responsible for producing the isoprenoid precursor IPP in many Gram-positive bacteria and eukaryotes, we constructed three strains of Staphylococcus aureus in which each of the mevalonate pathway genes is regulated by an IPTG inducible promoter. We used DNA microarrays to profile the transcriptional effects of downregulating the components of the mevalonate pathway in S. aureus and demonstrate that decreased expression of the mevalonate pathway leads to widespread downregulation of primary metabolism genes, an upregulation in virulence factors and cell wall biosynthetic determinants, and surprisingly little compensatory expression in other isoprenoid biosynthetic genes. We subsequently correlate these transcriptional changes with downstream metabolic consequences. We used microarrays to profile the transcriptional changes incurred when downregulating mvaS, mvaA, or mvaK in S. aureus. Keywords: stress response S. aureus mutants were generated in which mvaS, mvaA, or mvaK were placed under control of the IPTG-inducible Pspac promoter. These mutants, as well as wildtype RN4220 S. aureus, were grown with or without 1 mM IPTG, harvested in exponential phase, and their total RNA was extracted and hybridized to Affymetrix GeneChips. Experiments were done in triplicate.
2010-05-05 | E-GEOD-13424 | biostudies-arrayexpress
Project description:We have discovered that loss of wild-type p53 correlates with elevated expression of mevalonate pathway genes in murine liver cancer and in human tumors. Mechanistically p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene, which inhibits SREBP-2 maturation. In mice the increase in mevalonate gene expression occurs in premalignant p53-null hepatocytes at a stage when p53 is needed to actively suppress tumorigenesis. Either RNAi mediated suppression of key genes in the mevalonate pathway or pharmacological inhibition of its rate-limiting enzyme restricts the development of mouse hepatocellular carcinomas driven by p53 loss. Conversely, like p53 loss, ablation of ABCA1 promotes tumorigenesis in a murine model and is associated with increased SREBP-2 maturation. Our findings thereby demonstrate that repression of the mevalonate pathway is a crucial component of p53-mediated tumor suppression and outline the mechanism by which this occurs.
2018-10-23 | GSE121558 | GEO
Project description:Metastasis is an important factor affecting the prognosis and survival of bladder cancer (BLCA) patients. Our previous study found that the mevalonate pathway is associated with the migratory ability of bladder cancer cells, but the exact mechanism is unclear. Here, we found that BLCA patients with mevalonate pathway activation had a poorer prognosis. Inhibition of the mevalonate pathway (simvastatin or zoledronic acid) resulted in a significant decrease in the migratory ability of BLCA cells. Therefore, we used proteomics to detect simvastatin- or zoledronic acid-treated BLCA cells to explore the effect of the mevalonate pathway on key proteins in BLCA cells.
2024-09-09 | PXD048067 |