Davide Ruggero, PhD

Professor in Residence
Department of Urology
RuggeroD@Urology.ucsf.edu

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.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Human Genetics
Research Summary: 
Dynamics of translation control in gene expression, cancer, and disease

Websites

Publications: 

Non-invasive measurement of mTORC1 signaling with 89Zr-transferrin.

Clinical cancer research : an official journal of the American Association for Cancer Research

Truillet C, Cunningham JT, Parker MF, Huynh LT, Conn CS, Ruggero D, Lewis JS, Evans MJ

The 4E-BP-eIF4E axis promotes rapamycin-sensitive growth and proliferation in lymphocytes.

Science signaling

So L, Lee J, Palafox M, Mallya S, Woxland CG, Arguello M, Truitt ML, Sonenberg N, Ruggero D, Fruman DA

New frontiers in translational control of the cancer genome.

Nature reviews. Cancer

Truitt ML, Ruggero D

Cell type-specific abundance of 4EBP1 primes prostate cancer sensitivity or resistance to PI3K pathway inhibitors.

Science signaling

Hsieh AC, Nguyen HG, Wen L, Edlind MP, Carroll PR, Kim W, Ruggero D