MYC Deregulation in Primary Human Cancers

Kalkat, Manpreet; Melo, Jason De; Hickman, Katherine Ashley; Lourenco, Corey; Redel, Cornelia; Resetca, Diana; Tamachi, Aaliya; Tu, William B.; Penn, Linda Z.

doi:10.3390/genes8060151

Cited by 343 publications

(306 citation statements)

References 241 publications

(342 reference statements)

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“…More interestingly, two of the regions ( 7q21.12 and 8q24.22 ) were significantly amplified in malignant samples, which lead us to discover the association of MYC , a known marker of malignancy, with the development of IPMN. The amplification and deregulation of MYC have been reported in numerous cancer studies, and its key role in metabolism, cell cycle, the biogenesis of ribosomes, and consequently, in cell growth and proliferation makes it the perfect target and marker for malignancy in IPMN detection by PJD . This finding, combined with the correlation of mutation burden with grade, has strong potential to predict the progression of IPMNs to malignancy, and exome sequencing or whole genome sequencing analysis of PJD is useful to assess the malignant risk of IPMNs.…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas

et al. 2019

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Intraductal papillary mucinous neoplasm (IPMN) of pancreas has a high risk to develop into invasive cancer or co‐occur with malignant lesion. Therefore, it is important to assess its malignant risk by less‐invasive approach. Pancreatic juice cell‐free DNA (PJD) would be an ideal material in this purpose, but genetic biomarkers for predicting malignant risk from PJD are not yet established. We here performed deep exome sequencing analysis of PJD from 39 IPMN patients with or without malignant lesion. Somatic alterations and copy number alterations (CNAs) detected in PJD were compared with the histologic grade of IPMN to evaluate their potential as a malignancy marker. Somatic mutations of KRAS , GNAS , TP53 , and RNF43 were commonly detected in PJD of IPMNs, but no association with the histologic grades of IPMN was found. Instead, mutation burden was positively correlated with the histologic grade ( r = 0.427, P = 0.015). We also observed frequent copy number deletions in 17p13 ( TP53 ) and amplifications in 7q21 and 8q24 ( MYC ) in PJDs. The amplifications in 7q21 and 8q24 were positively correlated with the histologic grade and most prevalent in the cases of invasive carcinoma ( P = 0.002 and 7/11; P = 0.011 and 6/11, respectively). We concluded that mutation burden and CNAs detected in PJD may have potential to assess the malignant progression risk of IPMNs.

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Section: Discussionmentioning

confidence: 99%

Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas

et al. 2019

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“…c-Myc is one of the best-studied oncogenes promoting tumorigenesis in many tissues (Kress et al, 2015;Dejure & Eilers, 2017;Kalkat et al, 2017). It is frequently over expressed in cancer, correlates with tumor aggressiveness and poor clinical outcome (Nesbit et al, 1999;Beroukhim et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

AMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress

et al. 2018

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Although c-Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the mouse melanoma model to show that c-Myc is essential for tumor initiation, maintenance, and metastasis. c-Myc-expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c-Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c-Myc-positive melanoma cells activated and became dependent on the metabolic energy sensor AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c-Myc-expressing melanoma cells, while AMPK activation protected against cell death of c-Myc-depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early-stage human melanoma samples revealed an inverse correlation between C-MYC and patient survival, suggesting that C-MYC expression levels could serve as a prognostic marker for early-stage disease.

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“…We have previously shown that induction of the c‐Myc oncogene in a nontransformed epithelial cell line induces a profound change in the pool of secreted proteins, with IGFBP‐6 and IGFBP‐7 being markedly down‐regulated . Here we extended this observation to a cellular model for breast tumorigenesis, a cancer where c‐Myc is found frequently overexpressed and is associated with poor prognosis . We show that the human nontransformed mammary epithelial cell line (MCF10A) expressing the estrogen‐inducible c‐MycER chimera (MCF10A‐MycER) undergoes a concomitant induction of IGF‐I/IGF‐II and reduction of IGFBP‐6 secretion.…”

Section: Introductionmentioning

confidence: 71%

Paracrine recruitment and activation of fibroblasts by c‐Myc expressing breast epithelial cells through the IGFs/IGF‐1R axis

Vincenzo

Belli

Franco

et al. 2019

Intl Journal of Cancer

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Fibroblasts are among the most abundant stromal cells in the tumor microenvironment (TME), progressively differentiating into activated, motile, myofibroblast‐like, protumorigenic cells referred to as Cancer‐Associated Fibroblasts (CAFs). To investigate the mechanisms by which epithelial cells direct this transition, the early stages of tumorigenesis were exemplified by indirect cocultures of WI‐38 or human primary breast cancer fibroblasts with human mammary epithelial cells expressing an inducible c‐Myc oncogene (MCF10A‐MycER). After c‐Myc activation, the conditioned medium (CM) of MCF10A‐MycER cells significantly enhanced fibroblast activation and mobilization. As this was accompanied by decreased insulin‐like growth factor binding protein‐6 (IGFBP‐6) and increased insulin‐like growth factor‐1 and IGF‐II (IGF‐I, IGF‐II) in the CM, IGFs were investigated as key chemotactic factors. Silencing IGFBP‐6 or IGF‐I or IGF‐II expression in epithelial cells or blocking Insulin‐like growth factor 1 receptor (IGF‐1R) activity on fibroblasts significantly altered fibroblast mobilization. Exposure of WI‐38 fibroblasts to CM from induced MCF10A‐MycER cells or to IGF‐II upregulated FAK phosphorylation on Tyr397, as well as the expression of α‐smooth muscle actin (α‐SMA), features associated with CAF phenotype and increased cell migratory/invasive behavior. In three‐dimensional (3D)‐organotypic assays, WI‐38 or human primary fibroblasts, preactivated with either CM from MCF10A‐MycER cells or IGFs, resulted in a permissive TME that enabled nontransformed MCF10A matrix invasion. This effect was abolished by inhibiting IGF‐1R activity. Thus, breast epithelial cell oncogenic activation and stromal fibroblast transition to CAFs are linked through the IGFs/IGF‐1R axis, which directly promotes TME remodeling and increases tumor invasion.

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MYC Deregulation in Primary Human Cancers

Cited by 343 publications

References 241 publications

Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas

Genomic analysis of pancreatic juice DNA assesses malignant risk of intraductal papillary mucinous neoplasm of pancreas

AMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress

Paracrine recruitment and activation of fibroblasts by c‐Myc expressing breast epithelial cells through the IGFs/IGF‐1R axis

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