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Redox Biology Apr 2024Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor...
Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell sub-populations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress.
Topics: Humans; Female; Shc Signaling Adaptor Proteins; Breast Neoplasms; Src Homology 2 Domain-Containing, Transforming Protein 1; Oxidative Stress; Phenotype; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38211442
DOI: 10.1016/j.redox.2024.103028 -
Aging Jan 2024The global prevalence of breast cancer necessitates the development of innovative prognostic markers and therapeutic strategies. This study investigated the prognostic...
Deciphering the prognostic significance of anoikis-related lncRNAs in invasive breast cancer: from comprehensive bioinformatics analysis to functional experimental validation.
The global prevalence of breast cancer necessitates the development of innovative prognostic markers and therapeutic strategies. This study investigated the prognostic implications of anoikis-related long non-coding RNAs (ARLs) in invasive breast cancer (IBC), which is an area that has not been extensively explored. By integrating the RNA sequence transcriptome and clinical data from The Cancer Genome Atlas (TCGA) database and employing advanced regression analyses, we devised a novel prognostic model based on ARL scores. ARL scores correlated with diverse clinicopathological parameters, cellular pathways, distinct mutation patterns, and immune responses, thereby affecting both immune cell infiltration and anticipated responses to chemotherapy and immunotherapy. Additionally, the overexpression of a specific lncRNA, , significantly impeded the proliferation and migration, as well as possibly the anoikis resistance of breast cancer cells. These findings highlight the potential of the ARL signature as a robust prognostic tool and a promising basis for personalized IBC treatment strategies.
Topics: Anoikis; Prognosis; RNA, Long Noncoding; Computational Biology; Databases, Factual; Neoplasms
PubMed: 38189818
DOI: 10.18632/aging. -
Lab on a Chip Jan 2024Due to low numbers of circulating tumor cells (CTCs) in liquid biopsies, there is much interest in enrichment of alternative circulating-like mesenchymal cancer cell...
Due to low numbers of circulating tumor cells (CTCs) in liquid biopsies, there is much interest in enrichment of alternative circulating-like mesenchymal cancer cell subpopulations from tumor cultures for utilization within molecular profiling and drug screening. Viable cancer cells that are released into the media of drug-treated adherent cancer cell cultures exhibit anoikis resistance or anchorage-independent survival away from their extracellular matrix with nutrient sources and waste sinks, which serves as a pre-requisite for metastasis. The enrichment of these cell subpopulations from tumor cultures can potentially serve as an source of circulating-like cancer cells with greater potential for scale-up in comparison with CTCs. However, these live circulating-like cancer cell subpopulations exhibit size overlaps with necrotic and apoptotic cells in the culture media, which makes it challenging to selectively enrich them, while maintaining them in their suspended state. We present optimization of a flowthrough high frequency (1 MHz) positive dielectrophoresis (pDEP) device with sequential 3D field non-uniformities that enables enrichment of the live chemo-resistant circulating cancer cell subpopulation from an culture of metastatic patient-derived pancreatic tumor cells. Central to this strategy is the utilization of single-cell impedance cytometry with gates set by supervised machine learning, to optimize the frequency for pDEP, so that live circulating cells are selected based on multiple biophysical metrics, including membrane physiology, cytoplasmic conductivity and cell size, which is not possible using deterministic lateral displacement that is solely based on cell size. Using typical drug-treated samples with low levels of live circulating cells (<3%), we present pDEP enrichment of the target subpopulation to ∼44% levels within 20 minutes, while rejecting >90% of dead cells. This strategy of utilizing single-cell impedance cytometry to guide the optimization of dielectrophoresis has implications for other complex biological samples.
Topics: Humans; Cell Line, Tumor; Neoplastic Cells, Circulating; Pancreatic Neoplasms; Pancreas
PubMed: 38174422
DOI: 10.1039/d3lc00804e -
Journal of Cancer 2024Immunotherapy has greatly changed the treatment of advanced non-small cell lung cancer (NSCLC). Anoikis is a programmed cell death process associated with cancer....
Immunotherapy has greatly changed the treatment of advanced non-small cell lung cancer (NSCLC). Anoikis is a programmed cell death process associated with cancer. However, the correlation between anoikis-related genes and the tumor microenvironment (TME) features and immunotherapeutic outcome in NSCLC has not been fully explored. The bulk and single-cell transcriptome data of NSCLC were downloaded from TCGA and GEO databases. The distribution of anoikis-related genes on different cell types at the single-cell level was analyzed, and these genes specifically expressed by tumor cells and immunotherapy-related were further extracted. Next, the candidate gene CTNND1 was identified and its correlations with the TME features and immunotherapeutic outcome in NSCLC were explored in multiple public cohorts. Finally, an in-house cohort was used to determine the CTNND1 expression and immuno-correlation in NSCLC. At single-cell atlas, we found that anoikis-related genes expressed specifically in tumor cells of NSCLC. By intersecting anoikis-related genes, immunotherapy-associated genes, and the genes expressed in tumor cells, we obtained a special biomarker CTNND1. In addition, cell-cell communication analysis revealed that CTNND1+ tumor cells communicated with immune subpopulations frequently. Moreover, we found that high expression of CTNND1 was related to immuno-suppressive status of NSCLC. The expression of CTNND1 and its immuno-correlation were also validated, and the results showed that CTNND1 was highly expressed in NSCLC tissues and tumors with high CTNND1 expression accompanied with low CD8+ T cells infiltration. Overall, our study reported that CTNND1 can be considered as a novel biomarker for the predication of immunotherapeutic responses and a potential target for NSCLC therapy.
PubMed: 38169514
DOI: 10.7150/jca.89542 -
Journal of Extracellular Biology Oct 2023Associations between plasma membrane blebbing and metastatic progression have been widely reported. There are also reports of increased extracellular vesicle release...
Associations between plasma membrane blebbing and metastatic progression have been widely reported. There are also reports of increased extracellular vesicle release from cancer cells. Yet the ties between these closely related phenomena are incompletely understood. In this commentary, we remark on a recent finding on cellular membrane blebs in melanoma signaling. We discuss possible implications for cancer biology and draw parallels to knowns and unknowns in the relationships of extracellular vesicles and cancer progression.
PubMed: 38162121
DOI: 10.1002/jex2.112 -
Aging Dec 2023Anoikis is a speed-limited procedure to inhibit tumor metastasis during epithelial-mesenchymal transition (EMT). Previous studies have explored anoikis-related genes...
Anoikis regulator GLI2 promotes NC cell immunity escape by TGF-β-mediated non-classic hedgehog signaling in colorectal cancer: based on artificial intelligence and big data analysis.
BACKGROUND
Anoikis is a speed-limited procedure to inhibit tumor metastasis during epithelial-mesenchymal transition (EMT). Previous studies have explored anoikis-related genes (ARG) in predicting prognosis and distinguishing tumoral immunity in many types of cancer. However, the role of ARGs in regulating NK cell exhaustion (NKE) and in predicting chemotherapy sensitivity is not clear. Therefore, it is necessary to work on it.
METHODS
Gene expression profiles and clinical features are collected from TCGA and GEO, and data analysis is performed in R4.2.0.
RESULTS
The ARGs-based no-supervised learning algorithm identifies three ARG subgroups, amongst which the prognosis is different. WCGNA and Artificial intelligence (AI) are applied to construct an NKE-related drug sensitivity stratification and prognosis identification model in digestive system cancer. Pathways association analysis screens out GLI2 is a key gene in regulating NKE by non-classic Hedgehog signaling (GLI2/TGF-β/IL6). experiments show that down-regulation of GLI2 enhances the CAPE-mediated cell toxicity and accompanies with down-regulation of PD-L1, tumor-derive IL6, and snial1 whereas the expression of cleaved caspas3, cleaved caspase4, cleaved PARP, and E-cadherin are up-regulated in colorectal cancer. Co-culture experiments show that GLI2- decreased colorectal tumor cells lead to down-regulation of TIM-3 and PD1 in NK cells, which are restored by TGF-bate active protein powder. Besides, the Elisa assay shows that GLI2-decreased colorectal tumor cells lead to up-regulation of IFN-gamma in NK cells.
Topics: Humans; Anoikis; Artificial Intelligence; Cell Line, Tumor; Colorectal Neoplasms; Hedgehog Proteins; Interleukin-6; Nuclear Proteins; Transforming Growth Factor beta; Zinc Finger Protein Gli2
PubMed: 38159250
DOI: 10.18632/aging.205283 -
Heliyon Dec 2023The phenomenon of cell death is a vital aspect in the regulation of aberrant cells such as cancer cells. Anoikis is a kind of cell death that occurs when cells get... (Review)
Review
The phenomenon of cell death is a vital aspect in the regulation of aberrant cells such as cancer cells. Anoikis is a kind of cell death that occurs when cells get separated from the extracellular matrix. Some cancer cells can inhibit anoikis in order to progress metastasis. One of the key variables that might be implicated in anoikis resistance (AR) is viral infections. The most important viruses involved in this process are Epstein-Barr virus, human papillomavirus, hepatitis B virus, human herpes virus 8, human T-cell lymphotropic virus type 1, and hepatitis C virus. A better understanding of how carcinogenic viruses suppress anoikis might be helpful in developing an effective treatment for virus-associated cancers. In the current study, we review the role of the mentioned viruses and their gene products in anoikis inhibition.
PubMed: 38144298
DOI: 10.1016/j.heliyon.2023.e22598 -
Translational Oncology Feb 2024Thyroid carcinoma (THCA) is a tumor commonly occurring in the endocrine system, and its incidence rate is increasing yearly. Anoikis is a type of cell death involved in...
Thyroid carcinoma (THCA) is a tumor commonly occurring in the endocrine system, and its incidence rate is increasing yearly. Anoikis is a type of cell death involved in the carcinogenesis process. This study aimed to investigate the prognosis and immune correlations of anoikis in THCA. Our study used several bioinformatics algorithms (co-expression analysis, univariate and multivariate Cox analysis) to screen anoikis-related genes (ARGs) to construct risk models. Through receiver operating characteristic (ROC) curve, nomogram, and independent prognostic analysis found that the constructed model had ideal predictive value for THCA. The consensus clustering method was used to divide ARG patterns into three subgroups, and there were significant differences in survival among the three subgroups. The CIBERSORT algorithm demonstrated strong correlations among immune infiltrating cells, prognostic genes, and risk scores. Univariate and multivariate Cox analysis showed that CDKN2A is an independent prognostic gene. Basic experiments (immunohistochemistry, qRT-PCR, etc.) showed that the expression levels of CDKN2A mRNA and protein were highly expressed in THCA, which was consistent with the results of bioinformatics analysis. In vitro, the knockdown of CDKN2A significantly inhibited the proliferation and migration of THCA cells. In summary, our study utilized eight ARGs to construct an accurate risk model. ARGs, especially CDKN2A, play a crucial role in the occurrence and development of THCA and can become potential targets for treating THCA patients.
PubMed: 38141377
DOI: 10.1016/j.tranon.2023.101873 -
Cells Dec 2023Pre-clinical studies from the recent past have indicated that senescent cells can negatively affect health and contribute to premature aging. Targeted eradication of...
Pre-clinical studies from the recent past have indicated that senescent cells can negatively affect health and contribute to premature aging. Targeted eradication of these cells has been shown to improve the health of aged experimental animals, leading to a clinical interest in finding compounds that selectively eliminate senescent cells while sparing non-senescent ones. In our study, we identified a senolytic capacity of statins, which are lipid-lowering drugs prescribed to patients at high risk of cardiovascular events. Using two different models of senescence in human vascular endothelial cells (HUVECs), we found that statins preferentially eliminated senescent cells, while leaving non-senescent cells unharmed. We observed that the senolytic effect of statins could be negated with the co-administration of mevalonic acid and that statins induced cell detachment leading to anoikis-like apoptosis, as evidenced by real-time visualization of caspase-3/7 activation. Our findings suggest that statins possess a senolytic property, possibly also contributing to their described beneficial cardiovascular effects. Further studies are needed to explore the potential of short-term, high-dose statin treatment as a candidate senolytic therapy.
Topics: Animals; Humans; Aged; Cellular Senescence; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Endothelial Cells; Anoikis; Senotherapeutics
PubMed: 38132158
DOI: 10.3390/cells12242836 -
Scientific Reports Dec 2023Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene...
Pulmonary arterial hypertension (PAH) is characterized by endothelial cell (EC) dysfunction. There are no data from living patients to inform whether differential gene expression of pulmonary artery ECs (PAECs) can discern disease subtypes, progression and pathogenesis. We aimed to further validate our previously described method to propagate ECs from right heart catheter (RHC) balloon tips and to perform additional PAEC phenotyping. We performed bulk RNA sequencing of PAECs from RHC balloons. Using unsupervised dimensionality reduction and clustering we compared transcriptional signatures from PAH to controls and other forms of pulmonary hypertension. Select PAEC samples underwent single cell and population growth characterization and anoikis quantification. Fifty-four specimens were analyzed from 49 subjects. The transcriptome appeared stable over limited passages. Six genes involved in sex steroid signaling, metabolism, and oncogenesis were significantly upregulated in PAH subjects as compared to controls. Genes regulating BMP and Wnt signaling, oxidative stress and cellular metabolism were differentially expressed in PAH subjects. Changes in gene expression tracked with clinical events in PAH subjects with serial samples over time. Functional assays demonstrated enhanced replication competency and anoikis resistance. Our findings recapitulate fundamental biological processes of PAH and provide new evidence of a cancer-like phenotype in ECs from the central vasculature of PAH patients. This "cell biopsy" method may provide insight into patient and lung EC heterogeneity to advance precision medicine approaches in PAH.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Artery; Endothelial Cells; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Vascular Diseases; Wnt Signaling Pathway
PubMed: 38110438
DOI: 10.1038/s41598-023-48077-6