Davide Ruggero, PhD

Professor in Residence
Department of Urology
Primary Thematic Area
Cancer Biology & Cell Signaling
Secondary Thematic Area
Human Genetics
Research Summary
Dynamics of translation control in gene expression, cancer, and disease
[email protected]
[email protected]

Our research is centered on understanding the molecular mechanisms by which impairments in accurate control of mRNA translation, cell growth, and overall cellular protein synthesis rates lead to cancer. While it is commonly accepted that oncogenic signaling deregulates the transcriptional profile of neoplastic cells, our research has demonstrated a pivotal role for impairments in the translational efficiency of specific existing mRNA species at the post-transcription level towards cancer initiation. Global analysis of the deregulated proteome during cancer formation utilizing novel polysome microarrays pioneered by the Ruggero lab indicates that control of protein production provides a highly specific, robust, and rapid response to oncogenic stimuli. The mRNAs translationally affected encode proteins involved in cell-cell interaction, cell differentiation, signal transduction, and growth control. These findings strongly suggest that a radical shift in the composition of mRNAs associated with actively translating polysomes may lead to an immediate neoplastic phenotype upon an oncogenic lesion. Our research is uncovering that the direct effect on the proteome may serve as common mechanism elicited by multiple oncogenic signals (ie. PTEN/AKT/TOR, Ras, Myc) to cause cellular transformation and may overshadow the effect on the transcriptosome.

Our lab has generated the first mouse models for components of the translation machinery, including translation initiation factors and structural components of the ribosome, found muted in human disease and cancer. Utilizing biochemical, molecular, and genetic approaches within the context of these unique animal models, will continue to address: (1) Which specific steps of protein synthesis control, when deregulated, contribute to cancer initiation and what are the rate limiting steps in protein biosynthesis that are regulated by mitogens and growth factors? (2) What are the target mRNAs, which are affected by aberrant protein translation in neoplastic cells and do they contain specific signatures in their untranslated regions? (3) How is control of translation initiation coupled to cell growth and proliferation and can we apply this knowledge to the discovery of novel therapeutic agents that target the deregulated translation machinery in cancer? The implications of these results will be important in the design of a new generation of compounds that modulate the cellular proteome at the post-genomic level and act as cancer therapeutic agents.

Websites
Ruggero Lab

Publications

Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer.

Cancer discovery

Chesner LN, Polesso F, Graff JN, Hawley JE, Smith AK, Lundberg A, Das R, Shenoy T, Sjöström M, Zhao F, Hu YM, Linder S, Chen WS, Hawkins RM, Shrestha R, Zhu X, Foye A, Li H, Kim LM, Bhalla M, O'loughlin T, Kuzuoglu-Ozturk D, Hua JT, Badura ML, Wilkinson S, Trostel SY, Bergman AM, Ruggero D, Drake CG, Sowalsky AG, Fong L, Cooperberg MR, Zwart W, Guan X, Ashworth A, Xia Z, Quigley DA, Gilbert LA, Feng FY, Moran AE

Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer.

Nature communications

Macaya I, Roman M, Welch C, Entrialgo-Cadierno R, Salmon M, Santos A, Feliu I, Kovalski J, Lopez I, Rodriguez-Remirez M, Palomino-Echeverria S, Lonfgren SM, Ferrero M, Calabuig S, Ludwig IA, Lara-Astiaso D, Jantus-Lewintre E, Guruceaga E, Narayanan S, Ponz-Sarvise M, Pineda-Lucena A, Lecanda F, Ruggero D, Khatri P, Santamaria E, Fernandez-Irigoyen J, Ferrer I, Paz-Ares L, Drosten M, Barbacid M, Gil-Bazo I, Vicent S

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

Nature

Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, White KM, O'Meara MJ, Rezelj VV, Guo JZ, Swaney DL, Tummino TA, Huettenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Meyer B, Roesch F, Vallet T, Mac Kain A, Miorin L, Moreno E, Naing ZZC, Zhou Y, Peng S, Shi Y, Zhang Z, Shen W, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Lyu J, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Rakesh R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Liboy-Lugo J, Lin Y, Huang XP, Liu Y, Wankowicz SA, Bohn M, Safari M, Ugur FS, Koh C, Savar NS, Tran QD, Shengjuler D, Fletcher SJ, O'Neal MC, Cai Y, Chang JCJ, Broadhurst DJ, Klippsten S, Sharp PP, Wenzell NA, Kuzuoglu D, Wang HY, Trenker R, Young JM, Cavero DA, Hiatt J, Roth TL, Rathore U, Subramanian A, Noack J, Hubert M, Stroud RM, Frankel AD, Rosenberg OS, Verba KA, Agard DA, Ott M, Emerman M, Jura N, von Zastrow M, Verdin E, Ashworth A, Schwartz O, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor SN, Fraser JS, Gross JD, Sali A, Roth BL, Ruggero D, Taunton J, Kortemme T, Beltrao P, Vignuzzi M, García-Sastre A, Shokat KM, Shoichet BK, Krogan NJ

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing.

bioRxiv : the preprint server for biology

Gordon DE, Jang GM, Bouhaddou M, Xu J, Obernier K, O'Meara MJ, Guo JZ, Swaney DL, Tummino TA, Hüttenhain R, Kaake RM, Richards AL, Tutuncuoglu B, Foussard H, Batra J, Haas K, Modak M, Kim M, Haas P, Polacco BJ, Braberg H, Fabius JM, Eckhardt M, Soucheray M, Bennett MJ, Cakir M, McGregor MJ, Li Q, Naing ZZC, Zhou Y, Peng S, Kirby IT, Melnyk JE, Chorba JS, Lou K, Dai SA, Shen W, Shi Y, Zhang Z, Barrio-Hernandez I, Memon D, Hernandez-Armenta C, Mathy CJP, Perica T, Pilla KB, Ganesan SJ, Saltzberg DJ, Ramachandran R, Liu X, Rosenthal SB, Calviello L, Venkataramanan S, Lin Y, Wankowicz SA, Bohn M, Trenker R, Young JM, Cavero D, Hiatt J, Roth T, Rathore U, Subramanian A, Noack J, Hubert M, Roesch F, Vallet T, Meyer B, White KM, Miorin L, Agard D, Emerman M, Ruggero D, García-Sastre A, Jura N, von Zastrow M, Taunton J, Schwartz O, Vignuzzi M, d'Enfert C, Mukherjee S, Jacobson M, Malik HS, Fujimori DG, Ideker T, Craik CS, Floor S, Fraser JS, Gross J, Sali A, Kortemme T, Beltrao P, Shokat K, Shoichet BK, Krogan NJ

mTOR and Regulation of Translation.

Translation and Its Regulation in Cancer Biology and Medicine

Yoshinori Tsukumo, Mathieu Laplante, Armen Parsyan, Davide Ruggero, Bruno Fonseca

Kaplan et al. reply.

Nature

Rosandra N. Kaplan, Rebecca D. Riba, Stergios Zacharoulis, Anna H. Bramley, Loïc Vincent, Carla Costa, Daniel D. MacDonald, David K. Jin, Koji Shido, Scott A. Kerns, Zhenping Zhu, Daniel Hicklin, Yan Wu, Jeffrey L. Port, Nasser Altorki, Elisa R. Port, Davide Ruggero, Sergey V. Shmelkov, Kristian K. Jensen, Shahin Rafii, David Lyden, J. Wels