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NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma.

ABSTRACT: Although the existence of cancer stem cells (CSC) in adenoid cystic carcinoma (ACC) has been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization. Our objective was to isolate CSC from ACC and provide insight into signaling pathways that support their propagation.To isolate CSC from ACC and characterize them, we used ROCK inhibitor-supplemented cell culture, immunomagnetic cell sorting, andin vitro/in vivoassays for CSC viability and tumorigenicity.We identified in ACC CD133-positive CSC that expressed NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. CD133(+)ACC cells produced activated NOTCH1 (N1ICD) and generated CD133(-)cells that expressed JAG1 as well as neural differentiation factors NR2F1, NR2F2, and p27Kip1. Knockdowns ofNOTCH1, SOX10, and their common effectorFABP7had negative effects on each other, inhibited spheroidogenesis, and induced cell death pointing at their essential roles in CSC maintenance. Downstream effects ofFABP7knockdown included suppression of a broad spectrum of genes involved in proliferation, ribosome biogenesis, and metabolism. Among proliferation-linked NOTCH1/FABP7 targets, we identified SKP2 and its substrate p27Kip1. A ?-secretase inhibitor, DAPT, selectively depleted CD133(+)cells, suppressed N1ICD and SKP2, induced p27Kip1, inhibited ACC growthin vivo, and sensitized CD133(+)cells to radiation.These results establish in the majority of ACC the presence of a previously uncharacterized population of CD133(+)cells with neural stem properties, which are driven by SOX10, NOTCH1, and FABP7. Sensitivity of these cells to Notch inhibition and their dependence on SKP2 offer new opportunities for targeted ACC therapies.

SUBMITTER: Panaccione A

PROVIDER: S-EPMC4834904 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma.

Panaccione Alex A Chang Michael T MT Carbone Beatrice E BE Guo Yan Y Moskaluk Christopher A CA Virk Renu K RK Chiriboga Luis L Prasad Manju L ML Judson Benjamin B Mehra Saral S Yarbrough Wendell G WG Ivanov Sergey V SV

Clinical cancer research : an official journal of the American Association for Cancer Research 20160401 8

<h4>Purpose</h4>Although the existence of cancer stem cells (CSC) in adenoid cystic carcinoma (ACC) has been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization. Our objective was to isolate CSC from ACC and provide insight into signaling pathways that support their propagation.<h4>Experimental design</h4>To isolate CSC from ACC and characterize them, we used ROCK inhibitor-supplemented cell culture, immunomagnetic cell sorting, ...[more]

PMID: 27084744

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Project description:Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites. Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15-20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain. Both cancers lack targeted therapies owing to poor understanding of their molecular drivers.Gene expression profiling, immunohistochemical staining, western blot, RT-PCR, and in silico analysis of massive cancer data sets were used to identify novel markers and potential therapeutic targets for ACC and BBC. For the detection and comparison of gene signatures, we performed co-expression analysis using a recently developed web-based multi-experiment matrix tool for visualisation and rank aggregation.In ACC and BBC we identified characteristic and overlapping SOX10 gene signatures that contained a large set of novel potential molecular markers. SOX10 was validated as a sensitive diagnostic marker for both cancers and its expression was linked to normal and malignant myoepithelial/basal cells. In ACC, BBC, and melanoma (MEL), SOX10 expression strongly co-segregated with the expression of ROPN1B, GPM6B, COL9A3, and MIA. In ACC and breast cancers, SOX10 expression negatively correlated with FOXA1, a cell identity marker and major regulator of the luminal breast subtype. Diagnostic significance of several conserved elements of the SOX10 signature (MIA, TRIM2, ROPN1, and ROPN1B) was validated on BBC cell lines.SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features. Comparison between ACC/BBC and other cancers, such as neuroblastomaand MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity. SOX10 as a novel diagnostic marker for ACC and BBC provides important molecular insight into their molecular aetiology and cell origin. Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools.

Project description:PurposeAdenoid cystic carcinoma of the breast (ACCB) is a rare malignancy with a favorable prognosis. Little information exists regarding the impact of postoperative radiation therapy (RT) on survival outcome in patients with ACCB. This study aimed to evaluate the clinical significance of postoperative RT in ACCB.MethodsData of patients with ACCB were extracted from the Surveillance, Epidemiology, and End Results database (2000-2019). Univariate and multivariable Cox regression analyses were performed to identify prognostic factors. In addition, a nomogram model was constructed and internally validated for discrimination and calibration. The value of postoperative RT was respectively accessed in each risk subgroup according to nomogram-deduced individualized score.ResultsA total of 689 eligible patients were included in the analysis. Partial mastectomy was associated with an increased risk of death compared with partial mastectomy plus postoperative RT (P = 0.020), but total mastectomy with or without postoperative RT was comparable (P = 0.624). Then, in-depth analysis was performed for patients receiving breast-conserving therapy (n = 485, the training set vs. the testing set = 340 vs. 145). Age at diagnosis, histological grade, and T stage were identified as prognostic factors for overall survival (OS) (All P < 0.05). A nomogram was constructed to provide predictive accuracy toward individual OS rates of ACCB and to divide patients into different risk subgroups. Notably, compared with non-RT, postoperative RT significantly improved OS in the high-risk subgroup (P = 0.006 for the training set, and P = 0.013 for the overall population) but not in the low-risk subgroup (P = 0.807 for the training set, and P = 0.293 for the overall population), suggesting that these patients may be able to exempt from postoperative RT.ConclusionA robust and effective nomogram was developed to predict prognosis and assist in treatment decisions in patients with ACCB undergoing partial mastectomy.

Dataset Information

NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma.

Publications

NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma.

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