Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma

Morris, Zachary S.; McClatchey, Andrea I.

doi:10.1073/pnas.0902031106

Cited by 57 publications

(45 citation statements)

References 54 publications

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“…Then, DESI-MSI was used to examine the changes in relative abundances of specific metabolites in RCC and control kidney in situ (32,35). Metabolites of the glutaminolytic pathway, including glutamate and α-ketoglutarate, were identified, as well as an increase in relative abundances of ions corresponding to citrate, pyruvate, malate, and succinate in RCC compared with control samples.…”

Section: Significancementioning

confidence: 99%

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Shroff¹,

Eberlin

Dang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

220

217

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The MYC oncogene is frequently mutated and overexpressed in human renal cell carcinoma (RCC). However, there have been no studies on the causative role of MYC or any other oncogene in the initiation or maintenance of kidney tumorigenesis. Here, we show through a conditional transgenic mouse model that the MYC oncogene, but not the RAS oncogene, initiates and maintains RCC. Desorption electrospray ionization-mass-spectrometric imaging was used to obtain chemical maps of metabolites and lipids in the mouse RCC samples. Gene expression analysis revealed that the mouse tumors mimicked human RCC. The data suggested that MYC-induced RCC up-regulated the glutaminolytic pathway instead of the glycolytic pathway. The pharmacologic inhibition of glutamine metabolism with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide impeded MYC-mediated RCC tumor progression. Our studies demonstrate that MYC overexpression causes RCC and points to the inhibition of glutamine metabolism as a potential therapeutic approach for the treatment of this disease.MYC oncogene | renal cell carcinoma | desorption electrospray ionization mass spectrometry imaging | glutamine metabolism R enal cell adenocarcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport waste molecules from the blood to the urine. Most patients who present with advanced RCC have a dismal prognosis because RCC easily metastasizes and advances in therapy have been limited (1-3). A lack of transgenic models of RCC has made it difficult to identify and test new therapeutic modalities.The MYC pathway is activated in most cases of human RCC (4), genomically amplified in 5-10% of patients, overexpressed in 20% (5), and associated with a hereditary RCC syndrome (6) suggesting a causal role in the pathogenesis, but this has never been examined. Here, we report the development of a conditional transgenic mouse model for MYC-deregulated human RCC. The MYC oncogene contributes to tumorigenesis of many types of cancer through various mechanisms (7-10), including the regulation of proliferation and growth, protein and ribosomal biogenesis, changes in metabolism, lipid synthesis, and induction of angiogenesis (11)(12)(13)(14). MYC reprogramming can result in tumors that are addicted to glucose and/or glutamine for their energy metabolism (15-19). MYC directly regulates specific genes of the glycolytic and glutaminolytic pathways (15,17,20,21), including lactate dehydrogenase A (LDHA), glucose transporter 1 (Glut1), hexokinase 2 (HK2), phosphofructokinase-M 1 (PFKM1), and enolase 1 (Eno1) (21-23). Also, MYC coordinates genes involved in glutamine catabolism (SI MYC and Glutamine Catabolism). However, there has been no evidence to show that MYC overexpression directly drives and maintains RCC or how this occurs.Through our new transgenic mouse model, we showed that transgenic MYC, but not mutant RAS, overexpression in vivo rapidly initiates a highly aggressive RCC that histologi...

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Section: Significancementioning

confidence: 99%

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Shroff¹,

Eberlin

Dang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

220

217

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“…In this connection, a report of conditional knock-out mice of the Nf2 gene in the proximal convoluted tubules is noteworthy, because 100% of these mice developed RCC within 6 -10 months. 36 The NF2 gene is responsible for neurofibromatosis type 2, a familial cancer affected by bilateral eighth-cranial-nerve tumors, as well as meningiomas, shwannomas and gliomas. The NF2 gene encodes an actin-binding protein, merlin, which shows significant homology with ezrin, radixin and moesin, in addition to the 4.1 family proteins.…”

mentioning

confidence: 99%

Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma

Nagata

Sakurai-Yageta

Yamada

et al. 2011

Intl Journal of Cancer

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Renal clear cell carcinoma (RCCC) is the most frequent subpopulation of renal cell carcinoma and is derived from the proximal uriniferous tubules. We have previously reported that an actin‐binding protein, 4.1B/DAL‐1, is expressed in renal proximal tubules, whereas it is inactivated in 45% of RCCC by promoter methylation. In the lung and several epithelial tissues, 4.1B is shown to associate with a tumor suppressor protein, CADM1, belonging to the immunoglobulin‐superfamily cell adhesion molecules. Here, we demonstrate by immunohistochemistry that another member of the CADM‐family protein, CADM4, as well as 4.1B is expressed specifically in human proximal tubules, while CADM1 and 4.1N, another member of the 4.1 proteins, are expressed in the distal tubules. Immunoprecipitation analysis coupled with Western blotting revealed that CADM4 associated with 4.1B, while CADM1 associated with 4.1N in the lysate from normal human kidney, implicating that a cascade of CADM4 and 4.1B plays an important role in normal cell adhesion of the proximal tubules. On the other hand, CADM4 expression was lost or markedly reduced in 7 of 10 (70%) RCC cell lines and 28 of 40 (70%) surgically resected RCCC, including 10 of 16 (63%) tumors with T1a. CADM4 expression was more preferentially lost in RCCC with vascular infiltration (p = 0.04), suggesting that loss of CADM4 is involved in tumor invasion. Finally, introduction of CADM4 into an RCC cell line, 786‐O, dramatically suppressed tumor formation in nude mice. These findings suggest that CADM4 is a novel tumor suppressor candidate in RCCC acting with its binding partner 4.1B.

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“…More recently, the McClatchey lab has shown that inactivation of Nf2 flox alleles in the visceral endoderm driven by a specific Villin-Cre transgene induced an important lethality ranging from E17 to postnatal day 3. About 10% of the Villin-Cre;Nf2 flox/flox surviving pups developed kidney neoplasia (36). These data show that, depending on the site and time, Nf2 inactivation could either be pro-apoptotic or promote cell proliferation.…”

Section: Nf2mentioning

confidence: 71%

Preclinical Mouse Models of Neurofibromatosis

Shannon¹

2009

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information ABSTRACTThis report describes the past four years of research performed by a Consortium of investigators who were continuously funded by this Program since 1999 to develop, characterize, and utilize strains of mice that accurately model tumors found in persons with NF1 and NF2. This Consortium has generated many novel models of NF1 and NF2-associated tumors and has exploited these strains to investigate biologic and preclinical questions. The investigators have collaborated closely and have extensively shared expertise and reagents with each other and with NF researchers around the world. These mouse strains developed through this effort are a cornerstone of NF research and are instrumental to an effort by the Children's Tumor Foundation to organize and support a preclinical network for testing therapeutics that might benefit persons with NF1 and NF2 disease. SUBJECT TERMS INTRODUCTIONBenign and malignant tumors are a major cause of morbidity and mortality in individuals with NF1 and NF2. The NF1 and NF2 genes function as tumor suppressors in humans and mice. Although a great deal has been learned about the genetics, biochemistry, and cell biology of NF1 and NF2-associated tumors, it has proven difficult to translate these advances into new treatments. Accurate, well-characterized mouse models of NF-associated tumors are invaluable resources for achieving the long-term goal of bringing improved treatments to NF patients. The overall purpose of this consortium, which is now ending after 10 years, has been to develop such models that would serve as permanent resources for the scientific community. These efforts were timely for a number of reasons.First, advances in gene targeting technologies in the late 1990s made it feasible to introduce many types of alterations into the mouse germline. Indeed, investigators who pioneered this general strategy were awarded the Nobel Prize in Medicine in 2007. The members of this research consortium developed the initial strains of Nf1 and Nf2 mutant mice, which provided major insights into a number of the complications seen in human NF1 and NF2 patients. Through this consortium effort, we engineered conditional mutant alleles of both Nf1 and Nf2 and in used these novel strains to create tractable new models for biologic and preclinical studies. Second, investigating cells from these Nf1 and Nf2 mutant mice has provided numerous fundamental insights that are directly relevant to understanding deregulated growth in NF1 and NF2-deficient human cells. Genetic analys...

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Aberrant epithelial morphology and persistent epidermal growth factor receptor signaling in a mouse model of renal carcinoma

Cited by 57 publications

References 54 publications

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism

Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma

Preclinical Mouse Models of Neurofibromatosis

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