About

Rachelle Gaudet is the Chair of the Department of Molecular and Cellular Biology at Harvard University. She previously served as Head Tutor for the Biochemical Sciences Tutorial starting in 2005 and later as Faculty Director of the CPB concentration until 2023. Gaudet initiated the organization of the year-long centennial celebration of the tutorial program, emphasizing its enduring impact on scientific education and its role in shaping generations of students. Her leadership highlights her commitment to fostering scientific thinking, mentorship, and the integration of research and education within Harvard’s life sciences community.

Research topics

• Biology
• Cancer research
• Biochemistry
• Endocrinology
• Computational biology
• Immunology
• Cell biology
• Chemistry

Selected publications

• A SIRT5-induced metabolic switch underlies chemoresistance and ATR checkpoint dependence in triple-negative breast cancer

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-09

  articleOpen access

  Abstract Chemoresistance is the leading cause of poor prognosis in triple-negative breast cancer (TNBC), yet the underlying mechanisms remain unknown. To reveal metabolic drivers of de novo chemoresistance in TNBC, we analyzed pretreatment primary tumor biopsies, employing quantitative proteomics and metabolomics. Chemoresistant TNBCs exhibit hallmarks of oxidative phosphorylation (OXPHOS) and altered nucleotide metabolism linked to overexpression of the mitochondrial sirtuin, SIRT5. Through gain- and loss-of-function studies and stable isotope tracing, we demonstrate that SIRT5 induces a coordinated metabolic switch that redirects glycolysis to the pentose phosphate pathway, thereby augmenting nucleotide pools, while enhancing glutaminolysis to support OXPHOS. Mechanistically, SIRT5 enhances conversion of 6-phospho-D-gluconate to ribulose-5-phosphate through demalonylation of 6-phosphogluconate dehydrogenase (6-PGD), and coordinately activates oncogenic c-MYC to promote glutamine utilization and dependence. Concurrently, SIRT5-induced nucleotide deregulation induces replication stress and hypersensitivity to ATR checkpoint activation, and ATR inhibition synergistically reverses chemoresistance in TNBC. Thus, elevated SIRT5 orchestrates a coordinated metabolic switch to expand nucleotide pools and drive chemoresistance, while producing ATR checkpoint dependence that represents a metabolic vulnerability of SIRT5-overexpressing TNBC. Graphical Abstract

  PublisherDOI

• Novel multi-omic biomarkers to combat oocyte and ovarian aging

  GeroScience · 2026-02-03 · 1 citations

  articleSenior author
  PublisherDOI

• Abstract LB194: SIRT5 induces a metabolic switch to fuel nucleotide pools and chemoresistance in triple-negative breast cancer

  Cancer Research · 2026-04-17

  article

  Abstract Chemoresistance is a primary cause of relapse and mortality in triple-negative breast cancer (TNBC). To reveal the metabolic characteristics that contribute to de novo chemoresistance in human TNBC, we analyzed primary tumor biopsies prior to preoperative chemotherapy, employing quantitative mass spectrometry-based proteomics and metabolomics. Remarkably, our findings reveal that chemoresistant TNBCs exhibit a significant enrichment in metabolic traits associated with oxidative phosphorylation (OXPHOS) and altered nucleotide metabolism, which converge on the overexpression of SIRT5, a master regulator of mitochondrial metabolism. Notably, SIRT5 is frequently overexpressed in breast cancer due to copy number gains and amplifications. Through gain- and loss-of-function studies, we confirm that SIRT5 mediates chemoresistance through its catalytic activity. Using metabolomics and stable isotope tracing, we further demonstrate that SIRT5 induces a metabolic switch that redirects glycolysis to the pentose phosphate pathway (PPP), thereby replenishing nucleotide pools while enhancing glutaminolysis to support the tricarboxylic acid (TCA) cycle. Specifically, we show that SIRT5 catalyzes the conversion of 6-phospho-D-gluconate to ribulose-5-phosphate (R-5-P) by demalonylating the lysine residue (K59) on 6-phosphogluconate dehydrogenase (6-PGD). Furthermore, we reveal that SIRT5 drives cellular dependence on glutamine as a bioenergetic substrate through activation of oncogenic MYC. Dependency analysis reveals a significant genetic codependence between SIRT5 expression and ATR replication stress checkpoint activation. We find that the combination of ATR inhibitors and chemotherapeutic agents shows significant synergistic effects in reversing chemoresistance in TNBC. In summary, our findings illustrate that elevated SIRT5 orchestrates a coordinated metabolic switch to sustain the PPP and alter nucleotide pools, leading to replication stress and ATR checkpoint dependence. Simultaneously, it activates glutaminolysis to fuel the TCA cycle for bioenergetic demands. Thus, targeting ATR represents a crucial and selective metabolic vulnerability of SIRT5-overexpressing TNBC. Citation Format: Zuen Ren, Tiziano Bernasocchi, Kiran Kurmi, Chenxu (Vincent) Guo, Kevin Jiang, Eric Zaniewski, Garrett Lam, Kazi N. Islam, Shakchhi Joshi, Xin Li, Ilze Smidt, Agustina Maccio, Robert Morris, Bryce Ordway, Veerle I. Bossuyt, Gary X. Wang, Shinn-Huey S. Chou, Lee Zou, Ioannis Sanidas, Laura M. Spring, Michael Lawrence, Esther Rheinbay, Wilhelm Haas, Raul Mostoslavsky, Marcia C. Haigis, Leif W. Ellisen. SIRT5 induces a metabolic switch to fuel nucleotide pools and chemoresistance in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB194.

  PublisherDOI

• Stability and progressive differentiation of TFR cells are intrinsically and extrinsically controlled by TFH programs

  Nature Immunology · 2026-01-13 · 2 citations

  articleOpen access

  Follicular regulatory T (TFR) cells restrain follicular helper T (TFH) cell-mediated B cell responses to optimize humoral immunity while limiting autoimmunity. Here we assessed the developmental dynamics of TFR cells. We found that TFR cells undergo progressive differentiation through progenitor, early effector and late effector stages. Late effector TFR cells possessed inherent instability, and could lose expression of FoxP3 to become ExTFR cells. Expression of effector TFH programs in TFR cells preceded instability, a process that was mediated by Tcf7. A subset of ExTFR could be redeemed by re-expression of FoxP3. Extrinsically, TFH cells enhanced late effector TFR cell differentiation by diverting cells away from a default Prdm1/Blimp-1 fate to express Bcl6. Together, these data indicate that TFR cells are a dynamic and plastic cell subset, the differentiation of which is controlled by intrinsic and extrinsic programs that work together to form a feedback loop to control humoral immunity. Here the authors perform longitudinal sampling of lymphoid organs along with fate mapping and matched single-cell RNA sequencing and TCR sequencing to define the developmental dynamics of follicular regulatory T (TFR) cells. They find that TFR cells undergo clonal expansion and progressive differentiation in a process that requires follicular helper T cells.

  PublisherDOI

• Integrated analysis of transcriptional and metabolic responses to mitochondrial stress

  Cell Reports Methods · 2025-04-01 · 4 citations

  articleOpen accessSenior author

  Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.

  PublisherDOI

• The source of dietary fat influences anti-tumour immunity in obese mice

  Nature Metabolism · 2025-07-25 · 17 citations

  articleOpen access

  Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity.

  PublisherDOI

• PD-1 regulates tumor-infiltrating CD8+ T cells in both a cell-intrinsic and a cell-extrinsic fashion

  The Journal of Experimental Medicine · 2025-07-24 · 5 citations

  articleOpen access

  Although PD-1 inhibitors are FDA-approved for over 25 different cancers, the mechanisms contributing to response remain incompletely understood. To investigate how PD-1-deleted CD8+ T cells influence PD-1-expressing CD8+ T cells in the same tumor microenvironment, we developed an inducible PD-1 knockout (KO) model in which PD-1 is deleted on ∼50% of cells. PD-1 deletion beginning at day 7 after implantation of MC38 tumor cells led to robust tumor control. Remarkably, PD-1-expressing CD8+ T cells in the tumor had increased functionality similar to PD-1 KO CD8+ T cells. Using single-cell RNA-seq and TCR-seq, we found that the major transcriptional changes following PD-1 deletion were shared by PD-1 KO and PD-1-expressing CD8+ T cells, although PD-1 KO clones preferentially expanded. These data suggest PD-1 inhibitors not only exert cell-intrinsic effects but also may promote increased T cell function through non-cell-autonomous mechanisms, which has important implications for design of PD-1-based cancer immunotherapies.

  PublisherOA PDFDOI

• Transforming treatment paradigms: Focus on personalized medicine for high‐grade serous ovarian cancer

  CA A Cancer Journal for Clinicians · 2025-04-19 · 16 citations

  reviewOpen access

  High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of ovarian cancer, accounting for approximately 70% of all ovarian cancer cases and contributing significantly to the high mortality rates associated with this disease. Because of the asymptomatic nature of early stage disease, most patients are diagnosed at advanced stages when the cancer has already spread into the abdominal cavity, requiring complex and intensive surgical and chemotherapeutic interventions followed by maintenance therapies. Although a minority of cases are associated with well defined genetic syndromes, specific risk factors and a clear etiology in many cases remain elusive. HGSOC tumors are characterized by a high frequency of somatic gene copy number alterations, often associated with defects in homologous recombination repair of DNA. All attempts to introduce an effective screening for HGSOC to date have been unsuccessful. This review elucidates the complexities surrounding HGSOC and encompasses its etiology, epidemiology, classification, pathogenesis, and the current array of treatment strategies. Understanding molecular underpinnings is crucial for the development of targeted therapies and personalized multimodal treatment approaches in centralized therapeutic structures. This review also examines the importance of the tumor microenvironment. In addition, the authors' objective is to underscore the critical importance of placing the patient's perspective and diversity at the forefront of therapeutic strategies, thereby fostering a genuinely participatory decision-making process and ultimately improving patient quality of life.

  PublisherOA PDFDOI

• PP01.01 Oncogenic Signaling is Rewired to Support Nucleotide Metabolism in Acquired Resistance to Targeted Therapies in NSCLC

  Journal of Thoracic Oncology · 2025-04-01

  articleSenior author
  PublisherDOI

• Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer

  Science Immunology · 2025-05-09 · 22 citations

  articleOpen access

  High-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies.

  PublisherOA PDFDOI

Recent grants

• NIH Grant F32AG022775

  NIH · $139k · 2006

• Molecular mechanisms of Nutrient sensing in cancer

  NIH · $1.9M · 2017–2023

• NIH Grant R01AG032375

  NIH · $1.8M · 2015

• NIH Grant R01DK10329501A1

  NIH · $381k · 2019

• Defining mechanisms to promote antitumor immunity by modulating one-carbon metabolism

  NIH · $2.2M · 2023–2027

Frequent coauthors

• Arlene H. Sharpe

  Massachusetts General Hospital

  147 shared

• Shakchhi Joshi

  Massachusetts General Hospital

  117 shared

• Jared H. Rowe

  Harvard University

  85 shared

• Alison E. Ringel

  80 shared

• Haejin Yoon

  Ulsan National Institute of Science and Technology

  75 shared

• Joon Seok Park

  Samsung (South Korea)

  73 shared

• Megan E. Fung

  Harvard University

  65 shared

• Gordon J. Freeman

  64 shared

Labs

• Harvard’s Biochemical Sciences Tutorial ProgramPI

Education

• Ph.D., Molecular and Cell Biology

  University of California, San Francisco

  1997

• B.A., Molecular and Cellular Biology

  Harvard University

  1992