Identification of an ACK1/TNK2-based prognostic signature for colon cancer to predict survival and inflammatory landscapes.
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ABSTRACT:
SUBMITTER: Kong D
PROVIDER: S-EPMC8772074 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immunotherapy has achieved success in the treatment of esophageal squamous cell carcinoma (ESCC). However, studies concerning immune phenotypes within the ESCC microenvironment and their relationship with prognostic outcomes are limited. We constructed and validated an individual immune-related risk signature for patients with ESCC. We collected 196 ESCC cases, including 119 samples from our previous public data (GSE53624) to use as a training set and an independent cohort with 77 quantitative real-time polymerase chain reaction (qRT-PCR) data, which we used for validation. Head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC) cohorts were also collected for validation. A least absolute shrinkage and selection operator (LASSO) model and a stepwise Cox proportional hazards regression model were used to construct the immune-specific signature. The potential mechanism and inflammatory landscapes of the signature were explored using bioinformatics and immunofluorescence assay methods. This signature predicted different prognoses in clinical subgroups and the independent cohort, as well as in patients with HNSCC and LUSC. Further exploration revealed that the signature was associated with specific inflammatory activities (activation of macrophages and T-cell signaling transduction). Additionally, high-risk patients exhibited distinctive immune checkpoints panel and higher regulatory T cell and fibroblast infiltration. This signature served as an independent prognostic factor in ESCC. This was the first applicable immune-related risk signature for ESCC. Our results furnished new hints of immune profiling of ESCC, which may provide some clues to further optimize associated cancer immunotherapies.
| S-EPMC7773787 | biostudies-literature
Project description:Prostate cancer stem-like cells (PCSCs) are not only enriched in the CD44+PSA-/lo subpopulation but also employ androgen-independent signaling mechanisms for survival. CD44+ PCSCs defy androgen deprivation, resist chemo- and radiotherapy and are highly tumorigenic. Human prostate tissue microarray (TMA) staining revealed an increased membranous staining of CD44 in the luminal compartment in higher grade G7-G9 tumors versus staining of the basal layer in benign hyperplasia. To uncover tyrosine kinase/s critical for the survival of the CD44+PSA-/lo subpopulation, we performed an unbiased screen targeting 87 tyrosine kinases with gene specific siRNAs. Among a subset of tyrosine kinases crucial for PCSC survival, was a non-receptor tyrosine kinase, ACK1/TNK2, a critical regulator of castration resistant prostate cancer (CRPC) growth. Consistently, activated ACK1 as measured by phosphorylation at Tyr284 was significant in the CD44+PSA-/lo population. Conversely, pharmacological inhibition by ACK1 inhibitor, (R)-9bMS mitigated CD44+PSA-/lo sphere formation, overcame resistance to radiation-induced cell death, induced significant apoptosis in PCSCs and inhibited CD44+PSA-/lo xenograft tumor growth in castrated mice suggesting dependency of PCSCs on ACK1 for survival. Thus, blockade of ACK1/TNK2 could be a new therapeutic modality to target recalcitrant PCSCs.
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Project description:Background Bladder cancer is the tenth most common cancer worldwide. Valuable biomarkers in the field of diagnostic bladder cancer are urgently required. Method Here, the gene expression matrix and clinical data were obtained from The Cancer Genome Atlas (TCGA), GSE13507, GSE32894, and Mariathasan et al. Five prognostic genes were identified by the univariate, robust, and multivariate Cox's regression and were used to develop a prognosis-related model. The Kaplan–Meier survival curves and receiver operating characteristics were used to evaluate the model's effectiveness. The potential biological functions of the selected genes were analyzed using CIBERSORT and ESTIMATE algorithms. Cancer Therapeutics Response Portal (CTRP) and PRISM datasets were used to identify drugs with high sensitivity. Subsequently, using the bladder cancer (BLCA) cell lines, the role of TNFRSF14 was determined by Western blotting, cell proliferation assay, and 5-ethynyl-20-deoxyuridine assay. Results GSDMB, CLEC2D, APOL2, TNFRSF14, and GBP2 were selected as prognostic genes in bladder cancer patients. The model's irreplaceable reliability was validated by the training and validation cohorts. CD8+ T cells were highly infiltrated in the high-TNFRSF14-expression group, and M2 macrophages were the opposite. Higher expression of TNFRSF14 was associated with higher expression levels of LCK, interferon, MHC-I, and MHC-II, while risk score was the opposite. Many compounds with higher sensitivity for treating bladder cancer patients in the low-TNFRSF14-expression group were identified, with obatoclax being a potential drug most likely to treat patients in the low-TNFRSF14-expression group. Finally, the proliferation of BLCA cell lines was increased in the TNFRSF14-reduced group, and the differential expression was identified. TNFRSF14 plays a role in bladder cancer progression through the Wnt/β-catenin-dependent pathway. TNFRSF14 is a potential protective biomarker involved in cell proliferation in BLCA. Conclusion We conducted a study to establish a 5-gene score model, providing reliable prediction for the outcome of bladder cancer patients and therapeutic drugs to individualize therapy. Our findings provide a signature that might help determine the optimal treatment for individual patients with bladder cancer.
| S-EPMC8545590 | biostudies-literature
Project description:Long noncoding RNAs (lncRNAs) are increasingly recognized as decisive factors in the progression of head and neck squamous cell carcinoma (HNSCC), and they participate in the epithelial-mesenchymal transformation (EMT) of HNSCC. LncRNAs are closely related to the prognosis of patients with HNSCC; thus, it is essential to identify EMT-related lncRNAs with prognostic value for HNSCC. The coexpression network of EMT-related lncRNAs was constructed using The Cancer Genome Atlas (TCGA). An EMT-related eight-lncRNA-based prognostic signature was constructed using LASSO Cox regression and Cox proportional hazards analyses. Univariate and multivariate analyses and stratified prognosis confirmed that the prognostic signature was an independent predictive factor. Subsequently, we performed immune cell infiltration analysis, gene set enrichment analysis (GSEA), and single-sample GSEA (ssGSEA) pathway enrichment analysis to uncover the potential molecular mechanisms of prognostic differences in the high- and low-risk groups. Next, we discussed the relationship between the prognostic signature and immune checkpoint-related genes, their TIDE scores, and the sensitivity of common chemotherapeutics. Finally, we further verified the expression differences in lncRNAs that were included in our signature via RT-qPCR in eighteen paired tissues. In summary, this prognostic signature provides powerful prognostic biomarkers for HNSCC and could serve as a predictor for the sensitivity of common chemotherapeutics and immunotherapy responses as well as providing a reference for further personalized treatment.
| S-EPMC8902443 | biostudies-literature
Project description:The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and (33)P HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, (33)P HotSpot assay) and in vivo (IC50 < 2 ?M, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t(1/2) > 6 h).
| S-EPMC4605435 | biostudies-literature
Project description:The challenge of rapid macromolecular synthesis enforces the energy-hungry cancer cell mitochondria to switch their metabolic phenotypes, accomplished by activation of oncogenic tyrosine kinases. Precisely how kinase activity is directly exploited by cancer cell mitochondria to meet high-energy demand, remains to be deciphered. Here we show that a non-receptor tyrosine kinase, TNK2/ACK1 (tyrosine kinase non receptor 2), phosphorylated ATP5F1A (ATP synthase F1 subunit alpha) at Tyr243 and Tyr246 (Tyr200 and 203 in the mature protein, respectively) that not only increased the stability of complex V, but also increased mitochondrial energy output in cancer cells. Further, phospho-ATP5F1A (p-Y-ATP5F1A) prevented its binding to its physiological inhibitor, ATP5IF1 (ATP synthase inhibitory factor subunit 1), causing sustained mitochondrial activity to promote cancer cell growth. TNK2 inhibitor, (R)-9b reversed this process and induced mitophagy-based autophagy to mitigate prostate tumor growth while sparing normal prostate cells. Further, depletion of p-Y-ATP5F1A was needed for (R)-9b-mediated mitophagic response and tumor growth. Moreover, Tnk2 transgenic mice displayed increased p-Y-ATP5F1A and loss of mitophagy and exhibited formation of prostatic intraepithelial neoplasia (PINs). Consistent with these data, a marked increase in p-Y-ATP5F1A was seen as prostate cancer progressed to the malignant stage. Overall, this study uncovered the molecular intricacy of tyrosine kinase-mediated mitochondrial energy regulation as a distinct cancer cell mitochondrial vulnerability and provided evidence that TNK2 inhibitors can act as "mitocans" to induce cancer-specific mitophagy.Abbreviations: ATP5F1A: ATP synthase F1 subunit alpha; ATP5IF1: ATP synthase inhibitory factor subunit 1; CRPC: castration-resistant prostate cancer; DNM1L: dynamin 1 like; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Mdivi-1: mitochondrial division inhibitor 1; Mut-ATP5F1A: Y243,246A mutant of ATP5F1A; OXPHOS: oxidative phosphorylation; PC: prostate cancer; PINK1: PTEN induced kinase 1; p-Y-ATP5F1A: phosphorylated tyrosine 243 and 246 on ATP5F1A; TNK2/ACK1: tyrosine kinase non receptor 2; Ub: ubiquitin; WT: wild type.
| S-EPMC9980697 | biostudies-literature
Project description:BackgroundGlioma is the most common primary brain tumor with high mortality and poor outcomes. As a hallmark of cancers, inflammatory responses are crucial for their progression. The present study is aimed at exploring the prognostic value of inflammatory response-related genes (IRRGs) and constructing a prognostic IRRG signature for gliomas.Materials and methodsWe investigated the relationship between IRRGs and gliomas by integrating the transcriptomic data for gliomas from public databases. Differentially expressed IRRGs (DE-IRRGs) were identified in the GSE4290 cohort. Further, univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses were conducted to construct an IRRG signature using The Cancer Genome Atlas (TCGA) cohort. Gliomas from the Chinese Glioma Genome Atlas (CGGA) cohort were employed for independent validation. The performance of gene signature was assessed by survival and receiver operating characteristic curve analyses. The differences in clinical correlations, immune infiltrate types, immunotherapeutic response predictions, and pathway enrichment among subgroups were investigated via bioinformatic algorithms.ResultsIn total, 37 DE-IRRGs were determined, of which 31 were found to be associated with survival. Ultimately, eight genes were retained to construct an IRRG signature that further classified glioma patients into two groups; the high-risk group suffered a poorer outcome as compared to the low-risk group. Furthermore, the high-risk group was significantly correlated with several risk factors, including older age, higher tumor grade, IDH wild type, 1p19q noncodel, and MGMT unmethylation. The nomogram was constructed by integrating the risk scores and other independent clinical characteristics. Moreover, the high-risk group had a greater immune infiltration and was most likely to benefit from immunotherapy. Gene set enrichment analysis suggested that immune and oncogenic pathways were enriched in high-risk glioma patients.ConclusionWe constructed a signature composed of eight IRRGs for gliomas, which could effectively predict survival and guide decision-making for treatment.
| S-EPMC9132661 | biostudies-literature
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:Cervical cancer (CC) is a leading cause of cancer-related death in women. Limited studies have investigated whether immune-related genes (IRGs) or tumor immune microenvironment (TIME) could be indicators for CC prognoses. The aim of this study was to develop an improved prognostic signature for CC based on IRGs or TIME to predict survival and response to immune checkpoint inhibitors (ICIs). A prognostic signature was constructed using bioinformatics method and its predictive capability was validated. The mechanisms underlying the signature's predictive capability were explored with CIBERSORT algorithm and mutation analysis. Immunophenoscore (IPS) is validated for ICIs response, and was therefore explored in relation to the signature. A prognostic signature based on 11 IRGs was developed. A multivariate analysis revealed that the 11-IRG signature was an independent prognostic factor for overall survival (OS) and progression-free interval in CC patients. In the 11-IRG signature high-risk group, CD8 T cells and resting mast cells, which are found to associate with better OS in our study, were lower; activated mast cells, associated with poorer OS, were higher, compared with the low-risk group. An IPS analysis suggested that the 11-IRG signature low-risk group, which possessed a higher IPS, represented a more immunogenic phenotype that was more inclined to respond to ICIs. In short, an 11-IRG prognostic signature for predicting CC patients' survival and response to ICIs was firmly established. The predictive capability of this model in CC requires further testing with the goal of better prognostic stratification and treatment management.
| S-EPMC6844304 | biostudies-literature
Project description:The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.
| S-EPMC5512571 | biostudies-literature