Selected Recent Publications from the Lab
Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SWW, Grishin N, Laurent M, Xie X-J, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J (2012) BAP1 loss defines a new class of renal cell carcinoma Nat Genet 44(7): 751-759
A study that sets the foundation for the first molecular genetic classification of sporadic ccRCC.
Sivanand S, Peña-Llopis S, Zhao H, Kucejova B, Spence P, Pavia-Jimenez A, Yamasaki T, McBride DJ, Gillen J, Wolff NC, Morlock L, Lotan Y, Raj GV, Sagalowsky A, Margulis V, Cadeddu JA, Ross MT, Bentley DR, Kabbani W, Xie X-J, Kapur P, Williams NS, Brugarolas J (2012) A Validated Tumorgraft Model Reveals Activity of Dovitinib Against Renal Cell Carcinoma Science Translational Medicine 4, 137ra75
Animal models of kidney cancer are lacking. This report shows that human tumors implanted in mice (tumorgrafts) behave like the tumors in patients. Tumorgrafts reproduce the histology, gene expression, and mutations of renal cancer in patients. Furthermore, the treatment responsiveness of renal cancer in patients is preserved in mice. Using tumorgrafts as a model we show that an investigational agent, dovitinib, is superior to two drugs in use in the clinic.
Kinch L, Grishin NV, Brugarolas J (2011) Succination of Keap1 and Activation of Nrf2-Dependent Antioxidant Pathways in FH-Deficient Papillary Renal Cell Carcinoma Type 2 Cancer Cell 20:418-420
A preview with a model for how succination of Keap1 in FH-deficient tumors may affect its function.
Mata MA, Satterly N, Versteeg GA, Frantz D, Wei S, Williams N, Schmolke M, Peña-Llopis S, Brugarolas J, Forst CV, White MA, Garcia-Sastre A, Roth MG, Fontoura BM (2011) Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor Nat Chem Biol 7: 712-719
A chemical-genetic screen involving a library of 200,000 compounds identifies REDD1, a protein we previously showed is a critical regulator of mTORC1, as a host defense factor.
Peña-Llopis S, Vega-Rubin-de-Celis S, Schwartz JC, Wolff NC, Tran TAT, Zou L, Xie X-J, Corey DR, Brugarolas J (2011) Regulation of TFEB and V-ATPases by mTORC1 EMBO J 30(16): 3242-3258
A compelling experimental paradigm coupled with sophisticated bioinformatic and statistical analyses led us to discover that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis which is translocated in renal tumors, is regulated by mTORC1. The data provide a rationale for evaluating mTORC1 inhibitors in patients with translocation RCC.
Kucejova B, Peña-Llopis S, Yamasaki T, Sivanand S, Tran TAT, Alexander S, Wolff NC, Lotan Y, Xie X-J, Kabbani W, Kapur P, Brugarolas J (2011) Interplay between pVHL and mTORC1 pathways in clear-cell renal cell carcinoma Mol Can Res 9: 1255-1265
The two most important pathways in ccRCC are those governed by pVHL and mTORC1. This paper describes a negative feedback loop linking these two pathways that involves REDD1. In addition, the report implicates REDD1 and TSC1 as tumor suppressor genes in sporadic ccRCC.
Yamasaki T, Tran TA, Oz OK, Raj GV, Schwarz RE, Deberardinis RJ, Zhang X, Brugarolas J (2011) Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC Nat Rev Urol 8: 165-171
A tour de force to identify and exploit vulnerabilities in a tumor of a 24-year-old woman presenting with an unusual form of renal cancer. The first account of the use of a glycolytic inhibitor against a tumor deficient for a Krebs cycle enzyme and a report that is used by medical school instructors to teach students about bench-to-bedside research translation.
Wolff NC, Vega-Rubin-de-Celis S, Xie XJ, Castrillon DH, Kabbani W, Brugarolas J (2011) Cell-Type-Dependent Regulation of mTORC1 by REDD1 and the Tumor Suppressors TSC1/TSC2 and LKB1 in Response to Hypoxia Mol Cell Biol 31: 1870-1884
Using a variety of genetically engineered mouse strains including a novel Redd1-deficient mouse strain, the study reports the discovery that hypoxia signals are transduced to mTORC1 through different pathways in a tissue specific manner. The manuscript is also a cautionary tale about the undiscerning use of reporter mice.
Kucejova B, Sunny NE, Nguyen AD, Hallac R, Fu X, Peña-Llopis S, Mason RP, Deberardinis RJ, Xie XJ, Debose-Boyd R, Kodibagkar VD, Burgess SC, Brugarolas J (2011) Uncoupling hypoxia signaling from oxygen sensing in the liver results in hypoketotic hypoglycemic death Oncogene 30: 2147-2160
Following evidence that HIF regulates mitochondrial respiration in vitro, this report shows for the first time in vivo, that constitutive HIF activation in hepatocytes in mice is sufficient to suppress mitochondrial respiration resulting in a block in glucose and ketone production and causing the death of mice within days.
Wolff N, Kabbani W, Bradley T, Raj G, Watumull L, Brugarolas J (2010) Sirolimus and temsirolimus for epithelioid angiomyolipoma J Clin Oncol 28: e65-68
An account of how an understanding of tumor genetics and the availability of molecularly targeted drugs saved the life of a 24-year-old man presenting with an unusual kidney tumor and unstoppable bleeding.
Vega-Rubin-de-Celis S, Abdallah Z, Kinch L, Grishin NV, Brugarolas J*, Zhang X* (2010) Structural analysis and functional implications of the negative mTORC1 regulator REDD1 Biochemistry 49: 2491-2501 *Shared correspondence
A report of the crystal structure of REDD1 that challenges the conventional view of REDD1 action.
Zhou J, Brugarolas J, Parada LF (2009) Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1 Hum Mol Genet 18: 4428-4441
An evaluation of the role of PTEN and Tsc1 in renal cyst development.
Brugarolas J, Lotan Y, Watumull L, Kabbani W (2008) Sirolimus in metatastic renal cell carcinoma J Clin Oncol 26: 3457-3460
The first account on the use of sirolimus (rapamycin) for the treatment of renal cancer. A report of far-reaching consequences for individuals and societies that cannot afford temsirolimus (and everolimus).
Brugarolas J (2007) Renal-cell carcinoma - molecular pathways and therapies N Engl J Med 356: 185-187
An editorial accompanying two phase III clinical trials marking the advent of molecularly targeted approaches to renal cancer treatment.
Other Publications
Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG, Jr. (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex Genes Dev 18: 2893-2904
This manuscript reports the discovery that hypoxia signals are transduced to mTORC1 through the TSC1/TSC2 complex and REDD1, a protein of previously unknown function.
Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways Nat Med 10: 594-601
Brugarolas J, Kaelin WG, Jr. (2004) Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes Cancer Cell 6: 7-10
Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG, Jr. (2003) TSC2 regulates VEGF through mTOR-dependent and -independent pathways Cancer Cell 4: 147-158
The exploration of similarities between two otherwise divergent syndromes, VHL and TSC, led to the discovery that a functional link existed between HIF and mTORC1 and established a rationale for the evaluation of mTORC1 inhibitors against RCC.
Brugarolas J, Moberg K, Boyd SD, Taya Y, Jacks T, Lees JA (1999) Inhibition of cyclin-dependent kinase 2 by p21 is necessary for retinoblastoma protein-mediated G1 arrest after gamma-irradiation Proc Natl Acad Sci U S A 96: 1002-1007
Brugarolas J, Bronson RT, Jacks T (1998) p21 is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells J Cell Biol 141: 503-514
Brugarolas J, Jacks T (1997) Double indemnity: p53, BRCA and cancer Nat Med 3: 721-722
Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ (1995) Radiation-induced cell cycle arrest compromised by p21 deficiency Nature 377: 552-557
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