A5026583105- Cancer, Hypoxia, and Metabolism
- Metabolomics and Mass Spectrometry Studies
- Cancer, Lipids, and Metabolism
- RNA modifications and cancer
- Molecular Biology Techniques and Applications
- Bioinformatics and Genomic Networks
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- Renal cell carcinoma treatment
- RNA and protein synthesis mechanisms
- Gene expression and cancer classification
- Endoplasmic Reticulum Stress and Disease
- Viral Infectious Diseases and Gene Expression in Insects
- Genetic and Kidney Cyst Diseases
- Mitochondrial Function and Pathology
- Cellular transport and secretion
- Gene Regulatory Network Analysis
- Fungal and yeast genetics research
- Microtubule and mitosis dynamics
- Axon Guidance and Neuronal Signaling
- CAR-T cell therapy research
- Microbial Metabolic Engineering and Bioproduction
- Protein Kinase Regulation and GTPase Signaling
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
Massachusetts Institute of Technology
2019-2025
Baxter (United States)
2017-2025
Stanford University
2017-2025
Broad Institute
2023-2024
IIT@MIT
2021
Institute for Stem Cell Biology and Regenerative Medicine
2018
Although tumor growth requires the mitochondrial electron transport chain (ETC), relative contribution of complex I (CI) and II (CII), gatekeepers for initiating flow, remains unclear. In this work, we report that loss CII, but not CI, reduces melanoma by increasing antigen presentation T cell-mediated killing. This is driven succinate-mediated transcriptional epigenetic activation major histocompatibility complex-antigen processing (MHC-APP) genes independent interferon signaling....
Abstract Increased glucose uptake and metabolism is a prominent phenotype of most cancers, but efforts to clinically target this metabolic alteration have been challenging. Here, we present evidence that lactoylglutathione (LGSH), byproduct methylglyoxal detoxification, elevated in both human murine non-small cell lung cancers (NSCLC). Methylglyoxal reactive metabolite glycolysis reacts non-enzymatically with nucleophiles cells, including basic amino acids, reduces cellular fitness....
The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it established that the local abundance specific nutrients defines metabolic parameters for growth, factors guiding in compared to normal tissue blood remain poorly understood. To define these renal cell carcinoma (RCC), we performed quantitative metabolomic comprehensive lipidomic analyses interstitial fluid (TIF), adjacent kidney (KIF),...
Abstract Activating mutations in RAS GTPases drive many cancers, but limited understanding of less-studied interactors, and the specific roles different interactor paralogs, continues to limit target discovery. We developed a multistage discovery screening process systematically identify genes conferring RAS-related susceptibilities lung adenocarcinoma. Using affinity purification mass spectrometry, we generated protein–protein interaction map interactors pathway components containing...
Abstract CAR-T therapy is a promising, novel treatment modality for B-cell malignancies and yet many patients relapse through variety of means, including loss cells antigen escape. To investigate leukemia-intrinsic resistance mechanisms, we performed genome-wide CRISPR-Cas9 loss-of-function screens in an immunocompetent murine model acute lymphoblastic leukemia (B-ALL) utilizing modular guide RNA library. We identified IFN γ R/JAK/STAT signaling components processing presentation pathway as...
The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the initiated by recruitment ciliary vesicles to distal appendage mother centriole. However, mechanism directly captures yet be identified. an accompanying paper, we show protein, CEP89, important for vesicle recruitment, but not other steps (Tomoharu Kanie, Love, Fisher, Gustavsson, & Jackson, 2023). lack membrane binding motif in CEP89 suggests it may...
Abstract Acquiring nucleotides is essential for all dividing cells, and failure to maintain sufficient levels balance of impairs DNA replication. Eukaryotic cells meet nucleotide demands through either de novo synthesis or salvage precursors from the extracellular environment. Although it known that salvageable vary across tissues, contribution total acquisition in malignant remains underexplored. Using a mouse model B-cell acute lymphoblastic leukemia (B-ALL), we formulated...
Abstract Cancer cell metabolism is significantly influenced by microenvironmental factors such as nutrient availability, which can vary across different tissues and introduce exploitable therapeutic vulnerabilities. Notably, lipid availability particularly low in the brain compared to other tissues. To identify metabolic vulnerabilities of cells lipid-poor environments, we performed a CRISPR/Cas9 screen synthesis genes human cancer cultured lipid-rich versus media. Through this screen,...
Abstract Background: Esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) exhibit markedly different responses to treatment regimens, including chemotherapy, chemoradiation, immunotherapy. The transcription factor TP63 is expressed in ESCC notably absent EAC associated with differentiation expression of the GLUT1 glucose transporter cancers. Given its homology p53, a known tumor suppressor regulator metabolism, we sought determine whether p63 may confer distinct targetable...
The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which processes regulate the is not known. Here, we find that some cancer cells elevate response to serine deprivation by increasing mitochondrial respiration. Cancer respiration have higher production limiting conditions than with no response, independent of enzyme expression. Increases promote regardless whether environmentally limiting. Lipid also increase via...
Abstract Cancer metastasis is a major contributor to patient morbidity and mortality 1 , yet the factors that determine organs where cancers can metastasize are incompletely understood. In this study, we quantify absolute levels of over 100 nutrients available across multiple tissues in mice investigate how relates ability breast cancer cells grow different organs. We engineered with broad metastatic potential be auxotrophic for specific assessed their colonize then asked tumor growth...
Abstract Metastases arise from a subset of cancer cells that disseminate the primary tumor; however, factors contribute to proliferation in secondary site are incompletely understood. The ability thrive new tissue is influenced by genetic and epigenetic changes important for disease initiation progression, but these alone do not predict if where cancers metastasize. Specific types metastasize consistent subsets tissues, suggesting associated with tumor influence environments can grow. Using...
A challenge for screening new candidate drugs to treat cancer is that efficacy in cell culture models not always predictive of patients. One limitation standard a reliance on non-physiological nutrient levels propagate cells. Which nutrients are available can influence how cells use metabolism proliferate and impact sensitivity some drugs, but general assessment physiological affect response small molecule therapies lacking. To enable compounds determine the environment impacts drug...
ABSTRACT Control of cellular identity requires coordination developmental programs with environmental factors such as nutrient availability, suggesting that modulating aspects metabolism could alter cell state along differentiation trajectories. Here we find nucleotide depletion and DNA replication stress are common drivers progression across a variety normal transformed hematopoietic systems. stress-induced transitions begin during S phase independent ATR/ATM checkpoint signaling,...
Many metabolic phenotypes in cancer cells are also characteristic of proliferating nontransformed mammalian cells, and attempts to distinguish between resulting from oncogenic perturbation those associated with increased proliferation limited. Here, we examined the extent which changes corresponding KRAS expression differed epidermal growth factor (EGF)-driven human mammary epithelial (HMECs). Removal EGF culture medium reduced rates glucose/glutamine consumption control HMECs despite...
The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the initiated by recruitment ciliary vesicles to distal appendage mother centriole. However, mechanism directly captures yet be identified. an accompanying paper, we show protein, CEP89, important for thef vesicle recruitment, but not other steps (Tomoharu Kanie, Love, Fisher, Gustavsson, & Jackson, 2023). lack membrane binding motif in CEP89 suggests it may...