Transcriptomic data from cultured human fetal lung tip-derived organoids treated with MAPK inhibitors or AKT inhibitor
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PROVIDER: PRJNA869741 | ENA |
REPOSITORIES: ENA
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Project description:Human fetal lung tip cells were purifed from developing human lungs at pseudoglandular in vitro cultured as organoids. Whole transcriptomic data for 3 organoid lines received different signalling inhibitors were profiled by RNA seq.
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Project description:Cell-to-cell heterogeneity in gene expression can even be observed in the same type of cells, present in a similar environment. Transcriptional bursting is thought to be one of contributing factors to the heterogeneity, but it remains elusive how the kinetic properties of transcriptional bursting (e.g. burst size, burst frequency, and noise induced by transcriptional bursting) are regulated in mammalian cells. To unbiasedly identify genes regulating the kinetic properties of transcriptional bursting, we performed large-scale CRISPR/-Cas9 based screening and functional analysis, and found that Akt/MAPK signaling pathways are involved in the regulation of the kinetic properties of transcriptional bursting. To further characterize how these pathways affect mESC gene expression programs, we performed RNA-Seq analysis of mESCs cultured in standard (Std), 2i and Akt/MAPK signal-inhibitor containing medium (PD-MK). We found that expression levels of some genes encoding transcription elongation related factors were upregulated in PD-MK condition.
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Project description:Over 50% of human tumors display hyperactivation of the serine/threonine kinase AKT, but AKT inhibitors under clinical investigation lack therapeutic efficacy at tolerable doses and display significant on-target toxicities. Here we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition both with respect to biochemical and cellular suppression of AKT-driven phenotypes in breast cancer cell lines. A systematic growth inhibition screen across 288 cancer cell lines confirmed a substantially higher potency for INY-05-040 (median GI50adj = 1.1 µM) compared to our first-generation AKT degrader (INY-03-041; median GI50adj = 3.1 µM), with both compounds outperforming catalytic AKT inhibition with GDC-0068 (median GI50adj > 10 µM). Using multi-omic profiling and causal network integration in breast cancer cells, we demonstrate that the enhanced efficacy of INY-05-040 is associated with sustained suppression of AKT signaling, followed by a potent induction of the stress mitogen activated protein kinase (MAPK) cJun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low baseline JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Collectively, our study presents a systematic framework for mapping the network-wide signaling effects of therapeutically relevant compounds, revealing that INY-05-040 is a potent pharmacological suppressor of AKT signaling.
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Project description:Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair [MAPK inhibitors]
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Project description:Gene expression in Madin Darby canine kidney cells grown for 7 days to confluence on Transwell filters and exposed to HGF +/- inhibitors of the MAPK pathway (MAPK is one of the pathways activated when HGF binds to the CMET receptor tyrosine kinase). We used microarrays to detail the program of gene expression in MDCK cells and identified genes specifically regulated by HGF via the MAPK pathway. Keywords: signaling pathway analysis
2007-11-20 | GSE9435 | GEO
Project description:Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors. A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of melanoma patients. Using a drug screen targeting chromatin regulators in patient-derived 3D MAPK inhibitor-resistant melanoma cell cultures, we discovered that PARP inhibitors restore sensitivity to MAPK inhibitors, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARP inhibitors induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed EMT-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPK inhibitor-sensitive state. The combination of PARP and MAPK inhibitors synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating melanoma patients with PARP inhibitors in combination with MAPK inhibitors to abrogate acquired therapy resistance.
2023-08-24 | GSE221241 | GEO
Project description:Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide negative selection CRISPR/Cas9 screen with PI3K and AKT inhibitors to identify targetable synthetic lethalities in TNBC. We found that cholesterol homeostasis is a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived organoids of estrogen receptor (ER)-negative breast cancer. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBCs show dysregulated SREBP-2 activation in response to single agent or combination AKT inhibitor and pitavastatin, and this was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss promoted lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. This work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC.
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Project description:Human fetal lung tip cells were purifed from developing human lungs at pseudoglandular and canalicular stages and in vitro cultured as organoids. Whole transcriptomic data for each organoid line at different stages were profiled by RNA seq.
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Project description:Human fetal lung tip progenitor cells
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