ACRF Department of Cancer Biology and Therapeutics & Department of Genome Sciences Combined Seminar Series: Ribosomal biogenesis a novel therapeutic target for metastatic disease

Assistant Professor Theresa Vincent, Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden

Breast cancer is one of the most common cancers in women. Patients diagnosed with metastatic disease have an extremely poor prognosis, with a 10-year survival rate of only 5-10%. The mechanisms underlying the metastatic spread of cancer, including the orchestrated programs coordinating cell migration and dissemination throughout disease progression, are still unclear. Epithelial-to-Mesenchymal transition (EMT) is a critical program for cells to acquire pro-migratory and invasive properties which entails a reduction of proliferation with a concomitant decrease in junctional adhesion proteins and remodeling of cytoskeletal components to become more mesenchymal. In cancer, the EMT program has been linked to cell migration and metastasis as well as resistance to chemotherapies which target highly proliferative cells. A further understanding of the regulation and execution of the EMT program would expand the repertoire of potential treatments for aggressive cancers.

Proliferating cells are estimated to expend between 60-80% of their metabolic energy making ribosomes and translating messenger RNAs (mRNAs) into protein. Correspondingly, mechanisms regulating ribosomal RNA (rRNA) expression and protein synthesis are paramount to cell survival. Traditionally, the synthesis of rRNA has been linked to cellular proliferation. Our group has identified a new aspect of EMT cell physiology: in order to undergo EMT, cells induce rRNA synthesis in the absence of proliferation. Subsequently, we show that blocking de novo rRNA synthesis using Pol I assembly inhibitors and thus synthesis of new ribosomes is required for EMT and subsequent metastasis. These findings implicate changes in ribosome biogenesis and downstream ribosome functions in translation as critical determinants of disease progression. Further understanding of the role of Pol I in cancer, specifically in the regulation of metastasis, is necessary and would demonstrate that Pol I-directed therapies are an effective means of preventing cancer growth, progression and recurrence by impacting multiple levels of tumor progression, from the inhibition of primary tumor growth and invasion to stem cell maintenance.  

My scientific training over the last 17 years, ranging from master student to faculty member, has been conducted at the Karolinska Institute (KI) in Stockholm, Sweden and at Weill Cornell Medicine (WCM) in New York City. In these supportive environments I managed to establish myself as an independent investigator with my main core laboratory located at KI (currently consisting of one graduate student, one master student, two postdocs and a shared postdoc) and a smaller research unit at WCM where I am currently supervising two PhD students and a postdoc. This transatlantic effort has been instrumental in building and strengthen our research focus of the role of rRNA biology and ribosomes for metastatic disease at the interface of cancer biology research and the biophysics of mammalian translation regulation. The focus of my studies at both institutions has been the Epithelial-to-Mesenchymal Translation (EMT), a developmental program that enables cells to acquire pro-migratory and invasive properties. EMT, which entails a reduction of proliferation concomitant with a decrease in junctional adhesion proteins and remodeling of cytoskeletal components, has also been implicated in cancer metastasis. In my earlier studies, in mouse models of breast cancer, in which cells are induced to undergo EMT by TGFb, I identified a novel transcriptional repressor complex involving SNAIL1 and SMAD3/4 that suppresses the expression of junctional adhesion molecules such as Ecadherin, CAR and Occludin, particularly at the invasive fronts of human breast cancer (Vincent et al 2009, Nat. Cell. Biology). During my post-doctoral research in collaboration with Dr. David Allis at Rockefeller University, I headed a project that revealed an unanticipated and critical role of a histone-modifying enzyme, PAD4, in suppressing EMT through regulation of GSK3b (Stadler and Vincent, 2013, PNAS). In related pursuits, I have focused my efforts on understanding the regulation of ribosomal biogenesis during cancer growth and EMT. A key motivation for this research was my observation that GSK3b can suppress growth by interfering with the Pol I initiation complex assembly, which results in reduced ribosomal DNA (rDNA) gene transcription (Vincent 2008, Oncogene). My group has since demonstrated that Wnt5a signaling, a known mediator of tumor growth suppression in breast cancer also regulates rDNA expression through recruitment of the Disheveled-1 protein to the nucleolus, which displaces the Pol I transcription activator and deacetylase Sirtuin 7 (SIRT7) from rDNA genes to reduce transcription (Dass et al, 2016, PLOS Genetics). Inspired by these investigations, my pursuits, as an independent investigator has been to elucidate the role of rRNA biogenesis during EMT where cells obtain a non-proliferative, pro-migratory cell state. As described in the proposed research, our group has revealed that the EMT program is accompanied by an induction of rRNA synthesis that occurs in the absence of cellular proliferation. We have also shown that blocking de novo rRNA synthesis using Pol I assembly inhibitors is required for EMT and subsequent metastasis (Prakash et al, 2016, in revision, Nature). These key observations reveal a critical new aspect of EMT cell physiology, which we now aim to pursue. A long-term goal of these investigations is to elucidate whether this unanticipated feature of EMT can serve as a point of intervention for the clinical treatment of cancer metastasis for which therapies are currently a point of intervention for the clinical treatment of cancer metastasis for which therapies are currently lacking.

Date & time

3.30–4.30pm 21 September 2016


The Science Forum, Level 3, The John Curtin School of Medcial Research, Building 131 Garran Road, ANU


 Dr Nadine Hein

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