Mostoslavsky Lab

Inaugural Krantz Awards Recipient

2023 Breakthrough Award: Exploring cancer metabolism to direct treatments
Team: Nabeel Bardeesy, PhD and Raul Mostoslavsky, MD, PhD.

Learn more about the team's project and the Krantz Awards

Research Summary

Research in the Mostoslavsky laboratory focuses on the crosstalk between chromatin dynamics and cellular metabolism. Most of our previous work involves the Sir2 mammalian homolog known as SIRT6, an enzyme that plays a role in compacting the DNA scaffolding structure known as chromatin. Using a combination of in vitro and in vivo transgenic mice, our research indicates that SIRT6 modulates glucose metabolism and DNA repair and functions as a strong tumor suppressor gene. More recently, we have expanded our work to understand roles for metabolic heterogeneity in modulating chromatin dynamics and how cancer cells adapt to specific nutrient stressors. In particular, we have started to explore the unique adaptations of metastatic cells, and how they manage to set and grow in a new niche environment. We have found that they do so mainly through non-genetic adaptations, and we have identified novel genes uniquely upregulated as drivers of metastatic disease. We are currently exploring the molecular mechanisms by which these genes drive metastatic outgrowth.

Research Projects

DNA and histones are arranged in the nucleus in a highly condensed structure known as chromatin. Cellular processes that unwind the double helix—such as transcription, replication and DNA repair— have to overcome this natural barrier to DNA accessibility.

Multicellular organisms also need to control their use of cellular energy stores. Glucose metabolism plays a crucial role in organismal homeostasis, influencing energy consumption, cell proliferation, stress resistance and lifespan. Defective glucose utilization causes numerous diseases ranging from diabetes to an increased tendency to develop tumors. In order to respond appropriately to changes in energy status, cells need a finely tuned system to modulate chromatin dynamics iand to respond to metabolic cues. Reciprocally, chromatin changes necessary for cellular functions need to be coupled to metabolic adaptations.

Our lab is interested in understanding the influence of chromatin on nuclear processes (gene transcription, DNA recombination, and DNA repair) and the relationship between chromatin dynamics and the metabolic adaptation of cells. One of our interests is studying a group of proteins called SIRTs, the mammalian homologues of the yeast Sir2. In particular, our work has focused on the mammalian Sir2 homologue, SIRT6. In recent years, we have identified SIRT6 as a key modulator of metabolism, functioning as a histone H3K9 deacetylase to silence glycolytic genes; thus directing pyruvate to the TCA cycle to promote ATP synthesis. This function appears critical for glucose homeostasis, as SIRT6 deficient animals die early in life from hypoglycemia. Remarkably, we found SIRT6 to act as a tumor suppressor in multiple cancers, regulating cancer metabolism through mechanisms that bypass known oncogenic pathways. Cancer cells prefer fermentation (i.e., lactate production) to respiration, as described by biochemist and Nobel laureate Otto Warburg decades ago (i.e., the Warburg effect), yet the molecular mechanisms behind this metabolic switch remained a mystery. We found that SIRT6 is a critical epigenetic modulator of the Warburg effect, providing a long-sought molecular explanation to this phenomenon. Importantly, new work from the lab suggests that such metabolic adaptation occurs in a rare population of cells, indicating that tumors exhibit metabolic heterogeneity, and current work from the lab aims to understand whether such heterogeneity is dynamic, and whether it influences chromatin changes in cancer cells, as a mechanism to acquire “epigenetic plasticity”.

In recent years, we have broadened our research to explore roles of onecarbon metabolism (1C) in chromatin dynamics, particularly how the universal donor SAM is modulated in cells, exploring novel metabolic liabilities in cancer, new chromatin modifications, and new chromatin modulators of DNA repair. Importantly, past work on metabolism and chromatin in cancer has focused on primary tumors. We have started to explore the unique metabolic and epigenetic adaptation of metastatic cells, something that remains mostly unknown. In recent studies we have uncovered novel genes that are upregulated in metastatic cells, driving the survival of disseminated tumor cells in the new niche. These genes include metabolic enzymes and transporters, suggesting that metabolic adaptations will be key for metastatic cells to outgrowth, and we are currently exploring whether metabolic heterogeneity is a feature of metastasis as well. We use a number of experimental systems, including biochemical and biological approaches, as well as genetically engineered mouse models.

Specific projects:

1. Determining the role of SIRT6 in tumorigenesis and aging
2. Identifying novel histone modifications, and their roles in DNA repair
3. Determining molecular crosstalk between epigenetics and metabolism
4. Discovering non-genetic (epigenetic and metabolic) drivers of metastases

Research Positions

Postdoctoral Research Fellow (1)

A Postdoctoral Research Fellow position is available to study the molecular function of the mammalian Sirtuin proteins, focusing on the role of SIRT6 in the metabolic response against genotoxic stress. The candidate is expected to have a PhD in the biological sciences, and be highly motivated and tenacious as a scientist, with experience in molecular biology, cell biology and biochemical techniques. The Fellow will have simultaneous academic appointment at the Massachusetts General Hospital and Harvard Medical School. The Fellow will develop innovative mouse gene-targeting technology to study SIRT6 function in vivo as a regulator of lifespan, tumorigenesis and homeostasis, as well as biochemical approaches aimed to understand the influence of SIRT6 in chromatin structure and DNA repair. The laboratory is located within an active intellectual environment in the Cancer Center and Harvard Stem Cell Institute, with strong ties throughout the institution, Harvard, and the MIT communities.

To apply please email a brief cover letter and CV to:

Raul Mostoslavsky, MD, PhD
Associate Professor of Medicine
Massachusetts General Hospital
Harvard Medical School
Simches Research Building, CPZN 4200, 4th floor
Boston, MA 02114
Email: rmostoslavsky@mgh.harvard.edu

Publications

View a list of publications by researchers at the Mostoslavsky Laboratory

Selected Publications

Ferrer CM., Cho HM, Boon R, Bernasocchi T, Wong LP, Cetinbas M, Haggerty ER, Mitsiades I, Wojtkiewicz GR, McLoughlin DE, Aboushousha R, Abdelhamid H, Kugel S, Rheinbay E, Sadreyev R, Juric D, Janssen-Heininger YMW, and Mostoslavsky R. The glutathione S-transferase Gstt1 drives survival and dissemination in metastases. Nature Cell Biol. 2024, 26, 975-990.

Linder S, Bernasocchi T, MartinezPastor B, Sullivan KD, Galbraith MD, Lewis CA, Ferrer CM, Boon R, Silveira GG, Cho HM, Vidoudez C, Shroff S, Oliveira-Costa JP, Ross KN, Massri R, Matoba Y, Kim E, Rueda BR, Stott SL, Gottlieb E, Espinosa JM and Mostoslavsky R. Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells. Nature Metab. 2023, 5, 2131-2147.

Choi-J, Sebastian C, Ferrer C, Lewis C, Sade-Feldman M, Lasalle T, Gonye A, Lopez BCG, Abdelmoula W, Regan MS, Cetinbas, M, Pascual G, Wojtkiewicz GR, Silveira GG, Boon R, Ross KN, Tirosh I, Saladi SV, Ellisen LW, Sadreyev RI, Benitah SA, Agar NYR, Hacohen N, and Mostoslavsky R. A unique subset of glycolytic tumor propagating cells drives squamous cell carcinoma. Nature Metab. 2021, 3, 182-195.

Boon R, Silveira GG, and Mostoslavsky R.  Nuclear Metabolism and the regulation of the epigenome. Nat. Metabolism. 2020 Nov;2(11):1190-1203.

Kugel, S., Sebastian, C., Fitamant, J., Ross, K.N., Saha, S.K., Jain, E., Gladden, A., Arora, K.S., Kato, Y., Rivera, M.N., Ramaswamy, S., Sadreyev, R.I., Goren, A., Deshpande, V., Bardeesy, N., and Mostoslavsky, R. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell, 2016 Jun 2;165(6):1401-15.

Sebastian C, Zwaans BM, Silberman DM, Gymrek MA, Goren A, Zhong L, Ran O, Truelove J, Guimaraes AR, Toiber D, Cosentino C, Greenson JK, MacDonald AI, McGlynn L, Maxwell F, Edwards J, Giacosa S, Guccione E, Weisledder R, Bernstein BE, Regev A, Shiels PG, Lombard DB and Mostoslavsky R. The Histone Deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012 Dec 7;151(6):1185-99.

Our Researchers

Raul Mostoslavsky, MD, PhD

Group Members

• Tiziano Bernasocchi, PhD
• Hyo Min Cho, PhD
• Belen Machin, PhD
• Shweta Kumar, PhD
• Jose del Rio Pantoja*
• Nana Yaa Amoh*
• Nicole Smith, BSc†
• Dai Zhuanglin
• Janiru Liyanage††
• Safaa El Janan**

*Graduate student
† Lab Manager
†† Undergraduate student
** Summer student