Role of ACK1 condensates in STAT5 activation in LUSC cells
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ABSTRACT:
PROVIDER: PRJNA1213808 | ENA |
REPOSITORIES: ENA
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Project description:ACK1 is a non-receptor tyrosine kinase that phosphorylates multiple substrates involved in cancer progression. Additional regulatory mechanisms governing ACK1 activity remain to be elucidated. We demonstrate that ACK1 is frequently amplified and overexpressed in lung squamous cell carcinoma (LUSC). We found that ACK1 undergoes liquid-liquid phase separation (LLPS), a process dependent on the intrinsically disordered region (IDR, 96-156aa), but independent of its kinase activity. Our data also reveal that ACK1 phosphorylates STAT5 and promote STAT5 nuclear localization and transcriptional activity.
2025-07-02 | GSE287607 | GEO
Project description:Lung squamous cell carcinoma (LUSC) is associated with poor survival owing to the lack of advanced targeted therapies, due to the incomplete characterization of complex genetic profiles. Therefore, it is essential to elucidate the molecular mechanisms of LUSC via the mice model and human database to understand the LUSC pathogenesis. A LUSC BALB/c mice model was established using N-nitroso-tris-chloroethylurea (NTCU). After termination of mice, the lung tissues were subjected to RNA sequencing. First, DESeq2 was used to normalize the read count, followed by gene set enrichment analysis (GSEA) to identify the affected pathways in LUSC. Subsequently, the pathogenic single nucleotide polymorphism (SNP) was determined using Protein Variation Effect Analyzer (PROVEAN) and Sorting Intolerant From Tolerant (SIFT), following scores of < 0.05 and < -2.5, respectively, which were then functionally enriched using g:Profiler. The transcriptomic profile of human LUSC patients was obtained from The International Cancer Genome Consortium (ICGC) and analyzed. The impact of pathogenic simple somatic mutation in human LUSC was determined using the Combined Annotation Dependent Depletion (CADD) score, which was functionally enriched using g:Profiler. Additionally, the enriched pathway of LUSC patients with complete remission (responsive) was compared with those with disease progression or deceased (non-responsive) post-GSEA treatment. All pathway analysis was possibly referred to the Reactome database, and an adjusted p-value < 0.05 was considered statistically significant. Based on the transcriptomic analysis of LUSC mice, the top pathway enriched from the animal study and human LUSC revealed similarity in four major themes: cholesterol, cellular interaction, immune, and extracellular matrix dysregulation. Furthermore, the overrepresented pathways identified in LUSC patients were consistent with the four major themes dysregulated in LUSC tumors. This study identified several biological pathways that may contribute to LUSC development and potential targets for future LUSC therapy.
2024-12-31 | GSE240837 | GEO
Project description:Solid tumors are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of the effector T cells and its trafficking back to the tumor. The T cell activation is negatively regulated by C-terminal Src kinase (CSK), however, the exact mechanism of CSK’s T cell-restraining activity remains unknown. Here, we show that the primeval oncogenic tyrosine kinase, ACK1 dampens T-cell response by augmenting CSK activity through a novel Tyr18-phosphorylation. Ack1/Tnk2-knockout mice exhibited a loss of CSK Tyr18-phosphorylation and activation of CD8+ and CD4+ T cells, compromising ICB-resistant tumor growth. Further, ICB-treated Castration-resistant prostate cancer (CRPC) patients revitalized ACK1/pY18-CSK signaling, revealing it to be the critical molecular mechanism for ICB insensitivity. Consistently, ICB-resistant tumor growth was suppressed upon treatment with a new class of ACK1 small-molecule inhibitor, (R)-9b. Interestingly, (R)-9b caused increase in leukocyte attractant, CXCL10 in cancer cells, thus navigating newly activated T cells to the tumors, creating a `self-sabotaging loop’. Overall, harnessing unique dichotomous mode of ACK1 that controls immune response of the T cells, and cytokine levels in tumor microenvironment, provides an unprecedented opportunity to sensitize immune-resistance.
2022-09-01 | GSE211835 | GEO
Project description:Over-activation of oncogenes by aberrant expression of epigenetic modulators, overcoming cell cycle checkpoints and bestowing infinite multiplication potency acts as the mainstay of malignancy. We identified one such non-receptor tyrosine kinase ACK1 as an epigenetic regulator of cell cycle genes governing the G2/M transition of breast cancer cells. ACK1 was found to be over-activated (pY264-ACK1) in most of the breast cancer sub-types, independent of their hormone receptor status, as assessed by the Tissue-microarray analysis of nearly 400 breast cancer patient samples. ACK1 primed the epigenetic landscape surrounding the genes CCNB1, CCNB2 and CDC20 by depositing Y88-H4 histone activation marks, in turn initiating their efficient transcription. Pharmacological inhibition of ACK1 using small molecular inhibitor (R)-9b not only reversed this transcriptional potential but also sensitized the cells to a G2/M arrest, culminating in breast cancer cell death and tumor regression in in vivo xenograft models of breast cancer. Further, ACK1 was also found to modulate expression of the gene CXCR4, circumventing breast cancer metastasis on ACK1 ablation. In addition, ACK1 inhibition was also found to counteract the resistance of RB1 deficient breast cancer cells to the CDK4/6 inhibitor palbociclib, overcoming road blocks to conventional therapeutics. Overall, our data warrants the identification of ACK1 as an epigenetic controller of genes essential for the successful establishment and progression of breast cancer and signifies development of therapeutics against ACK1 to combat intrinsic and acquired breast cancer resistance.
2023-05-23 | GSE203231 | GEO
Project description:Over-activation of oncogenes by aberrant expression of epigenetic modulators, overcoming cell cycle checkpoints and bestowing infinite multiplication potency acts as the mainstay of malignancy. We identified one such non-receptor tyrosine kinase ACK1 as an epigenetic regulator of cell cycle genes governing the G2/M transition of breast cancer cells. ACK1 was found to be over-activated (pY264-ACK1) in most of the breast cancer sub-types, independent of their hormone receptor status, as assessed by the Tissue-microarray analysis of nearly 400 breast cancer patient samples. ACK1 primed the epigenetic landscape surrounding the genes CCNB1, CCNB2 and CDC20 by depositing Y88-H4 histone activation marks, in turn initiating their efficient transcription. Pharmacological inhibition of ACK1 using small molecular inhibitor (R)-9b not only reversed this transcriptional potential but also sensitized the cells to a G2/M arrest, culminating in breast cancer cell death and tumor regression in in vivo xenograft models of breast cancer. Further, ACK1 was also found to modulate expression of the gene CXCR4, circumventing breast cancer metastasis on ACK1 ablation. In addition, ACK1 inhibition was also found to counteract the resistance of RB1 deficient breast cancer cells to the CDK4/6 inhibitor palbociclib, overcoming road blocks to conventional therapeutics. Overall, our data warrants the identification of ACK1 as an epigenetic controller of genes essential for the successful establishment and progression of breast cancer and signifies development of therapeutics against ACK1 to combat intrinsic and acquired breast cancer resistance.
2023-05-23 | GSE203230 | GEO
Project description:TCGA Analysis of DNA Methylation for LUSC using Illumina Infinium HumanMethylation450 platform EXP-598 Assay Type: Methylation Provider: Illumina Array Designs: jhu-usc.edu_TCGA_HumanMethylation450 Organism: Homo sapiens (ncbitax) Tissue Sites: Lung Material Types: Control Analyte, Solid normal_tissue, organism_part, Primary solid_tumor Disease States: Lung Squamous Cell Carcinoma, NOT SPECIFIED
2015-05-14 | E-GEOD-68825 | biostudies-arrayexpress
Project description:TCGA Analysis of DNA Methylation for LUSC using Illumina Infinium HumanMethylation450 platform
2015-05-14 | GSE68825 | GEO
Project description:BCL11A is upregulated in lung squamous cell carcinoma (LUSC) but not in lung adenocarcinoma (LUAD). BCL11A interacts with SOX2 at protein level. ChIP-Seq experiment was performed for BCL11A and SOX2 in LUSC LK-2 control or BCL11A-KD cell line in order to identify their role in LUSC pathology.
2018-07-05 | E-MTAB-6958 | biostudies-arrayexpress
Project description:Transcriptional profiling of mouse osteoclasts comparing control osteoclasts from Stat5 flox mice with osteoclasts from Stat5 cKO mice. Two-condition experiment, Stat5 flox cells vs. Stat5 cKO cells
2013-12-09 | E-GEOD-51283 | biostudies-arrayexpress
Project description:Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK pY18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.
2023-03-11 | PXD037546 | Pride