Protein modification by ubiquitination has emerged as a critical regulatory event in virtually all aspects of cell biology. Ubiquitination is a reversible process, and ubiquitin moieties can be removed from polypeptides by deubiquitinating enzymes (DUBs). TGF-β is a cytokine with a key role in tissue homeostasis and cancer. In advanced tumours TGF-β switches from a tumour suppressor role to one as an oncogenic factor by inducing pro-invasive and pro-metastatic responses. We have recently identified a number of DUBs, which are overexpressed in glioblastoma, breast and ovarian cancers that act as potent activators of TGF-β pathway. Our lab is interested in studying the regulation of these DUBs on the TGF-β pathway and their role in cancer progression.
TGF-β is essential for embryogenesis and tissue homoeostasis in multicellular organisms. Furthermore, in advanced cancers TGF-β can act as an oncogenic factor and according to growing clinical evidence, TGF-β can be considered a therapeutic target in cancer. Ubiquitin modification of the TGF-β signaling pathway is emerging as a key mechanism of TGF-β pathway control. However the role of deubiquitinating enzymes (DUBs), which mediate the removal and processing of ubiquitin is less well understood. Using a genome wide RNAi loss-of-function screen I have identified multiple DUBs as key activators of TGF-β activity including USP15 and OTUD. There have been a number of interesting discoveries related to USP15 and the TGF-β pathway including the discovery that USP15 binds to a deubiquitinates a number of different components in the TGF-β pathway, including the transcription factor SMAD2, preventing promoter recognition. Furthermore, I have found that USP15 can bind to the SMAD7-SMURF2 complex leading to TGF-β receptor deubiquitination and stabilization. However, as part of an unknown negative feedback loop TGF-β induces the dissociation of USP15 from the SMAD7-SMURF2 complex leading to degradation of the TGF-β receptor and loss of TGF-β signal and pathway activation. My lab is presently focused on trying to identify novel feedback loops that might limit TGF-β inhibitor sensitivity restricting its role as a potential therapeutic approach.
In addition to elucidating the roles of deubiquitinating enzymes in the TGF-β pathway we are highly interested in identifying the potential roles of deubiquitinating enzymes and other small enzyme families in the mechanisms of resistance to targeted therapeutics in breast cancer including the anti-HER2 compounds Lapatinib and Herceptin and various PI3K inhibitors presently being used in early phase clinical trials. Using previously identified model systems we plan to perform synthetic lethal interaction screens to identify new druggable targets that permit combined pharmacological inhibition in molecularly defined breast cancer subsets.
- Iyengar PV, Jaynes P, Rodon L, Lama D, Law KP, Lim YP, Verma C, Seoane J, Eichhorn PJ. USP15 regulates SMURF2 kinetics through C-lobe mediated deubiquitination. Sci Rep. 2015 Oct 5;5:14733. doi: 10.1038/srep14733.
- Eichhorn PJ, Serra V, García-García C, Prudkin L, Sánchez G, Rodríguez O, Parra JL, Marlow S, Prat A, Arribas J, Hahn WC, Kim SY, Baselga J. p90RSK mediates resistance to PI3K-pathway inhibitors in breast cancer. J Clin Invest. 2013 Jun 3;123(6):2551-63. doi: 10.1172/JCI66343.
- Eichhorn PJ, Rodón L, Gonzàlez-Juncà A, Dirac A, Gili M, Martínez-Sáez E, Aura C, Barba I, Peg V, Prat A, Cuartas I, Jimenez J, García-Dorado D, Sahuquillo J, Bernards R, Baselga J, Seoane J. USP15 stabilizes TGF-β receptor I and promotes oncogenesis through the activation of TGF-β signaling in glioblastoma. Nat Med. 2012 Feb 19;18(3):429-35. doi: 10.1038/nm.2619.
- Eichhorn PJ, Scaltriti M, Cortés J, Prudkin L, Aura C, Jiménez J, Chandarlapaty S, Serra V, Prat A, Ibrahim YH, Guzmán M, Gili M, Rodríguez O, Rodríguez S, Pérez J, Green SR, Mai S, Rosen N, Hudis C, Baselga J. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3761-6. doi: 10.1073/pnas.1014835108. Epub 2011 Feb 14.
- Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, Markman B, Rodriguez O, Guzman M, Rodriguez S, Gili M, Russillo M, Parra JL, Singh S, Arribas J, Rosen N, Baselga J. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 2011 Jun 2;30(22):2547-57. doi: 10.1038/onc.2010.626. Epub 2011 Jan 31.
- Eichhorn PJ, Baselga J. HER2 signatures in breast cancer: ready to go to print? J Clin Oncol. 2010 Apr 10;28(11):1809-10. doi: 10.1200/JCO.2009.26.7146. Epub 2010 Mar 15. No abstract available.
- Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res. 2008 Nov 15;68(22):9221-30. doi: 10.1158/0008-5472.CAN-08-1740.
- Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008 Oct 1;68(19):8022-30. doi: 10.1158/0008-5472.CAN-08-1385.
- Eichhorn PJ, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta. 2009 Jan;1795(1):1-15. doi: 10.1016/j.bbcan.2008.05.005. Epub 2008 Jun 3. Review.
- Eichhorn PJ, Creyghton MP, Wilhelmsen K, van Dam H, Bernards R. A RNA interference screen identifies the protein phosphatase 2A subunit PR55gamma as a stress-sensitive inhibitor of c-SRC. PLoS Genet. 2007 Dec;3(12):e218.
|Affiliations||Principal Investigator, Cancer Science Institute of Singapore, NUS
NUS Assistant Professor, Department of Pharmacology, Yong Loo Lin School of Medicine, NUS
|csipjae[at]nus.edu.sg / phcpjae[at]nus.edu.sg|
|Institute||Degree (if applicable)||Year(s)|
|University of Western Ontario||B.Sc||1996|
|University of Newcastle upon Tyne||Ph.D.||2001|
|•||Principal Investigator, Cancer Science Institute of Singapore, NUS||2013 – Present|
|•||Assistant Professor , Department of Pharmacology, Yong Loo Lin School of Medicine, NUS||2013 – Present|
|•||Instructor of Medicine, Dr. Jose Baselga, Harvard Medical School||2010 – 2012|
|•||Assistant in Genetics, Dr. Jose Baselga, Massachusetts General Hospital||2010 – 2012|
|•||Postdoctoral fellow, Lab of Dr. Jose Baselga, Vall d’Hebron Institut de Oncologia||2006 – 2010|
|•||Postdoctoral fellow, Lab of Rene Bernards, Netherlands Cancer Institute||2001 – 2006|
Patrick William JAYNES
Elucidation of the role of novel deubiquitinating enzymes in the TGF-B pathway.
My project focuses on the identification of deubiquitinating enzymes in the PI3K pathway.
Research exploring the role of deubiquitinating enzymes in the MAPK pathway.