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Massimo F. Loda, MD
Pathologist, Brigham and Women's Hospital
Professor of Pathology, Emeritus, Harvard Medical School

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115

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Research Narrative:

     The ubiquitin system regulates the degradation of key intracellular proteins including p27.  The selective degradation of a given protein through ubiquitination involves the activation of a signaling cascade that results in the covalent attachment of a poly-ubiquitin chain to protein target.  The formation of a poly-ubiquitin chain, acts as a signal for degradation by the proteasome.  The enzymatic cascade responsible for ubiquitin conjugation can be reversed by de-ubiquitinating enzymes or isopeptidases.

     With the help, among other sources, of an RO1 focused on isopeptidases, my laboratory focused on possible interactors of isopeptidases in order to identify potential substrates.  First, we focused on the de-ubiquitinating enzyme Unp and determined that it interacts with the retinoblastoma protein product (DeSalle et al, Oncogene, 2001, 20, 5538-42).  More recently, we have shown that the isopeptidase USP2a is androgen responsive and over expressed in prostate tumors compared to adjacent normal prostate tissue.  In order to identify targets of the isopeptidase USP2a, we utilized affinity chromatography and mass spectrometry experiments. Fatty acid synthase (FASN) was identified as an interactor of USP2a. Utilizing gene expression profiling and tissue microarrays, we have also shown that FASN is overexpressed in prostate cancer (Rossi et al Mol Cancer Res 2003) and that its increased expression is associated with aggressive disease.  More recently, we have published a multidisciplinary study (immortalized cells, transgenic mice and large epidemiologic databases analyzed by in situ techniques on tissue microarrays) demonstrating that FASN is a bona fide oncogene (Migita et al, JNCI, 2009). Furthermore, we have shown that USP2 interacts with FASN, and siRNA against USP2a result in the induction of apoptosis of prostate tumor cells (Graner et al Cancer Cell, 2004).  Thus, inhibitors of USP2a may prove to be useful therapeutic tools.  We have now determined that USP2a is itself oncogenic in vitro and in vivo. A manuscript has been published in Cancer Res reporting these findings (Priolo et al, 2006). This was co-submitted at the time with two other manuscripts, one describing the interaction between USP2a and mdm2 and the other revealing the crystal structure of USP2a bound to Ubiquitin (EMBO Journal and Structure, 2006). We are currently analyzing the connection between USP2a overexpression and expression of Myc signatures in prostate adenocarcinomas, mediated by specific miRNAs. In addition, we have discovered that USP2a is implicated in the de-ubiquitination and re-cycling to membrane of the EGFR receptor tyrosine kinase. These manuscripts are in preparation. Finally, experiments to assess the metabolic profiling in immortalized prostate cells transformed with FASN and compared to those transformed with oncogenes such as MYC and myristilated Akt, are under way.


Lab Members:
Elisa Benedettini, PhD, Postdoctoral Research Fellow
Giuseppe Fedele, MD, Postdoctoral Research Fellow
Zhiqian Liu, PhD, Postdoctoral Research Fellow
Rosina Lis, MD, PhD, Postdoctoral Research Fellow
Emanuele Palescandolo, PhD, Postdoctoral Research Fellow
Carmen Priolo, MD, PhD, Postdoctoral Research Fellow
Shamini Selvarajah, PhD, Postdoctoral Research Fellow
Giorgia Zadra, PhD, Postdoctoral Research Fellow

Publications (Pulled from Harvard Catalyst Profiles):

1. Randall EC, Zadra G, Chetta P, Lopez BGC, Syamala S, Basu SS, Agar JN, Loda M, Tempany CM, Fennessy FM, Agar NYR. Molecular characterization of prostate cancer with associated Gleason score using mass spectrometry imaging. Mol Cancer Res. 2019 Feb 11.

2. Ahearn TU, Peisch S, Pettersson A, Ebot EM, Zhou CK, Graff RE, Sinnott JA, Fazli L, Judson GL, Bismar TA, Rider JR, Gerke T, Chan JM, Fiorentino M, Flavin R, Sesso HD, Finn S, Giovannucci EL, Gleave M, Loda M, Li Z, Pollak M, Mucci LA. Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease. Carcinogenesis. 2018 Dec 31; 39(12):1431-1437.

3. Zadra G, Ribeiro CF, Chetta P, Ho Y, Cacciatore S, Gao X, Syamala S, Bango C, Photopoulos C, Huang Y, Tyekucheva S, Bastos DC, Tchaicha J, Lawney B, Uo T, D'Anello L, Csibi A, Kalekar R, Larimer B, Ellis L, Butler LM, Morrissey C, McGovern K, Palombella VJ, Kutok JL, Mahmood U, Bosari S, Adams J, Peluso S, Dehm SM, Plymate SR, Loda M. Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer. Proc Natl Acad Sci U S A. 2019 01 08; 116(2):631-640.

4. Wang Z, Cao S, Morris JS, Ahn J, Liu R, Tyekucheva S, Gao F, Li B, Lu W, Tang X, Wistuba II, Bowden M, Mucci L, Loda M, Parmigiani G, Holmes CC, Wang W. Transcriptome Deconvolution of Heterogeneous Tumor Samples with Immune Infiltration. iScience. 2018 Nov 30; 9:451-460.

5. Elfandy H, Armenia J, Pederzoli F, Pullman E, Pertega-Gomes N, Schultz N, Viswanathan K, Vosoughi A, Blattner M, Stopsack KH, Zadra G, Penney KL, Mosquera JM, Tyekucheva S, Mucci LA, Barbieri C, Loda M. Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate. Mol Cancer Res. 2019 Feb; 17(2):446-456.

6. Penney KL, Loda M, Stampfer MJ. Re: Melissa Assel, Anders Dahlin, David Ulmert, et al. Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening. Eur Urol 2018;73:961-7. Eur Urol. 2019 Mar; 75(3):e54-e55.

7. Zadra G, Loda M. Metabolic Vulnerabilities of Prostate Cancer: Diagnostic and Therapeutic Opportunities. Cold Spring Harb Perspect Med. 2018 Oct 01; 8(10).

8. Stopsack KH, Gonzalez-Feliciano AG, Peisch SF, Downer MK, Gage RA, Finn S, Lis RT, Graff RE, Pettersson A, Pernar CH, Loda M, Kantoff PW, Ahearn TU, Mucci LA. A Prospective Study of Aspirin Use and Prostate Cancer Risk by TMPRSS2:ERG Status. Cancer Epidemiol Biomarkers Prev. 2018 Oct; 27(10):1231-1233.

9. Sowalsky AG, Ye H, Bhasin M, Van Allen EM, Loda M, Lis RT, Montaser-Kouhsari L, Calagua C, Ma F, Russo JW, Schaefer RJ, Voznesensky OS, Zhang Z, Bubley GJ, Montgomery B, Mostaghel EA, Nelson PS, Taplin ME, Balk SP. Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations. Cancer Res. 2018 Aug 15; 78(16):4716-4730.

10. Larimer BM, Dubois F, Bloch E, Nesti S, Placzek M, Zadra G, Hooker JM, Loda M, Mahmood U. Specific 18F-FDHT Accumulation in Human Prostate Cancer Xenograft Murine Models Is Facilitated by Prebinding to Sex Hormone-Binding Globulin. J Nucl Med. 2018 Oct; 59(10):1538-1543.