About

Jarrod Marto is a Professor of Chemistry in the School of Arts & Sciences and also holds the position of Professor of Biochemistry & Molecular Genetics in the School of Medicine. His research focuses on understanding the complex interactions between proteins, nucleotides, and metabolites within cells and tissues, particularly in the context of human disease. His laboratory develops and employs mass spectrometry, chemical, and genetic tools to investigate how DNA alterations and pathological insults influence cellular biochemical and signaling networks, with the goal of identifying therapeutic targets and developing molecular diagnostics for early detection, prognosis, and patient stratification. Marto's work involves leveraging quantitative proteomic data, including protein expression, isoform regulation, biochemical interactions, and post-translational modifications, to explore molecular mechanisms in disease and to identify new chemical probes and drug targets. His multidisciplinary and collaborative approach integrates synthetic and medicinal chemistry, structural and chemical biology, functional genomics, computational bioinformatics, and advanced instrumentation to support proteome-scale analyses in cell lines, clinical tissues, and single-cell contexts.

Research topics

• Biology
• Genetics
• Cell biology
• Cancer research
• Computational biology
• Chemistry
• Biochemistry
• Botany
• Molecular biology

Selected publications

• MassIVE MSV000100749 - SEC62-mediated control of HLA-E enables immune evasion in Diffuse Large B-Cell Lymphoma

  2026-01-01

  datasetOpen access1st authorCorresponding
  OA PDFDOI

• Inhibition of USP7 Destabilizes the Noncanonical PRC1.1 Complex and Induces Neuroblastoma Differentiation

  Molecular Cancer Research · 2026-03-19

  articleOpen access

  Pediatric cancers are frequently driven by genomic alterations that result in impaired differentiation during development. To identify complex-level dependencies required for differentiation in neuroblastoma, a pediatric cancer of the developing peripheral nervous system, we curated a list of protein complexes using the CORUM database and mined the Dependency Map (DepMap) using gene set enrichment analysis. This analysis identified the non-canonical PRC1.1 complex, which represses transcriptional activity through ubiquitination of histone 2A, lysine 119 (H2AK119Ub), as a selectively enriched dependency in neuroblastoma. Knockout of PRC1.1 subunits reduced neuroblastoma growth by inducing a neuronal differentiation program. While no known direct inhibitors of PRC1.1 exist, co-dependency analysis identified that the deubiquitinase USP7 strongly correlated with PRC1.1 dependency. Treatment with XL177A, a small molecule inhibitor of USP7, significantly reduced neuroblastoma growth in both cellular and animal models. Integrated RNA- and ChIP-sequencing showed that both PRC1.1 knockout and USP7 inhibition resulted in highly correlated transcriptional alterations and reduced H2AK119Ub deposition on chromatin, suggesting that USP7 inhibition reduced neuroblastoma growth through a PRC1.1-dependent mechanism. Mechanistically, global proteomics and ubiquitinomics revealed that USP7 inhibition disrupted non-canonical PRC1 complex assembly, resulting in destabilization of PRC1.1 and subsequent proteolysis. Our findings expand our understanding of the chromatin complexes required to maintain a de-differentiated state in neuroblastoma and suggest the therapeutic potential for USP7 inhibitors in the treatment of this disease. Implications: Our study reveals the potential for utilizing USP7 inhibitors to target epigenetic repression of differentiation programs in neuroblastoma by reducing PRC1 activity.

  PublisherOA PDFDOI

• Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2

  Science · 2025-11-27 · 5 citations

  articleOpen access

  The mechanistic target of rapamycin (mTOR) protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2 :: Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved among at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.

  PublisherOA PDFDOI

• TMET-20. Lipid-dependent regulation of lineage specification and tumor growth In H3K27M-mutant gliomas

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract H3K27M-mutant gliomas are lethal pediatric brain tumors driven by progenitor-like cells that subvert normal differentiation but retain some developmental plasticity, as evidenced by the presence of partially differentiated, non-tumorigenic H3K27M-positive cells within the tumor mass. This progenitor-to differentiated fate transition is also induced by the common cell culture supplement, serum. However, the identity of the pro-differentiation serum component is a key unanswered question. Through integrated lipidomic, chromatin, and single-cell transcriptomic analyses, we identify n-3 polyunsaturated fatty acids (n3-PUFAs) as the key serum and dietary components necessary and sufficient to induce differentiation of H3K27M glial progenitors. Remarkably, dietary enrichment of n3-PUFAs triggers this developmental shift in H3K27M-mutant glioma orthotopic models, reduces tumor burden, and increases survival. These findings uncover a previously unrecognized role for n3-PUFAs in governing glioma cell fate with promising therapeutic implications. Ongoing studies are focused on elucidating the molecular mechanisms whereby n3-PUFAs drive this differentiation program.

  PublisherOA PDFDOI

• PRM-LIVE with Trapped Ion Mobility Spectrometry and Its Application in Selectivity Profiling of Kinase Inhibitors

  UNC Libraries · 2025-10-10

  articleOpen access

  Parallel reaction monitoring (PRM) has emerged as a popular approach for targeted protein quantification. With high ion utilization efficiency and first-in-class acquisition speed, the timsTOF Pro provides a powerful platform for PRM analysis. However, sporadic chromatographic drift in peptide retention time represents a fundamental limitation for the reproducible multiplexing of targets across PRM acquisitions. Here, we present PRM-LIVE, an extensible, Python-based acquisition engine for the timsTOF Pro, which dynamically adjusts detection windows for reproducible target scheduling. In this initial implementation, we used iRT peptides as retention time standards and demonstrated reproducible detection and quantification of 1857 tryptic peptides from the cell lysate in a 60 min PRM-LIVE acquisition. As an application in functional proteomics, we use PRM-LIVE in an activity-based protein profiling platform to assess binding selectivity of small-molecule inhibitors against 220 endogenous human kinases.

  PublisherDOI

• Leveraging relaxation-optimized 1H–13CF correlations in 4-19F-phenylalanine as atomic beacons for probing structure and dynamics of large proteins

  Nature Chemistry · 2025-05-05 · 7 citations

  articleOpen access
  PublisherOA PDFDOI

• Pharmacologic interrogation of USP28 cellular function in p53 signaling

  Cell chemical biology · 2025-09-01 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Impact of BRCA mutations, age, surgical indication, and hormone status on the molecular phenotype of the human Fallopian tube

  Nature Communications · 2025-03-26 · 2 citations

  articleOpen access

  The human Fallopian tube (FT) is an important organ in the female reproductive system and has been implicated as a site of origin for pelvic serous cancers, including high-grade serous tubo-ovarian carcinoma (HGSC). We have generated comprehensive whole-genome bisulfite sequencing, RNA-seq, and proteomic data of over 100 human FTs, with detailed clinical covariate annotations. Our results challenge existing paradigms that extensive epigenetic, transcriptomic and proteomic alterations exist in the FTs from women carrying heterozygous germline BRCA1/2 pathogenic variants. We find minimal differences between BRCA1/2 carriers and non-carriers prior to loss of heterozygosity. Covariates such as age and surgical indication can confound BRCA1/2-related differences reported in the literature, mainly through their impact on cell composition. We systematically document and highlight the degree of variations across normal human FT, defining five groups capturing major cellular and molecular changes across various reproductive stages, pregnancy, and aging. We are able to associate gene, protein, and epigenetic changes with these and other clinical covariates, but not heterozygous BRCA1/2 mutation status. This sheds new light into prevention and early detection of tumorigenesis in populations at high-risk for ovarian cancer. The human Fallopian tube (FT) is implicated as a site of origin for pelvic serous cancers. Here the authors conduct multi-omics analysis on over 100 FTs. The results challenge the assumption that BRCA1/2 mutation carriers exhibit significant molecular alterations in normal FTs before loss of heterozygosity (LOH) occurs, and suggest that tumorigenesis in BRCA1/2 carriers requires LOH or secondary genetic events rather than haploinsufficiency alone.

  PublisherOA PDFDOI

• Overcoming EGFR resistance by monovalent and bident inhibitors targeting Cys775

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-02

  articleOpen access

  Covalent targeting of EGFR cysteine 797 by osimertinib is one of the most successful breakthroughs in targeted therapy, fundamentally transforming the treatment landscape for non-small cell lung cancer (NSCLC) patients. However, resistance driven by mutation of C797 remains a major clinical challenge. Developing novel covalent strategies beyond C797 targeting presents a compelling opportunity for next-generation EGFR inhibitors. We first demonstrated that cysteine 775, located deep within the ATP-binding pocket, is accessible by a rationally designed covalent molecule ZNL-3, which as the first-in-class covalent cysteine 775 inhibitor exhibited strong efficacy in osimertinib-resistant mouse models. To further enhance resilience to resistance-causing mutations, we developed a dual-warhead, bident compound-YNW-1-which covalently targets both cysteine 775 and 797 simultaneously. YNW-1 is the first intramolecular lock to exhibit balanced reactive efficiency on both cysteines, rendering single-site mutations ineffective to confer resistance. The discovery of ZNL-3 and YNW-1 represents significant advancements in EGFR-targeted drug development, and further optimization toward clinical translation is a worthwhile strategy. SIGNIFICANCE: This study establishes the therapeutic potential of an EGFR covalent inhibitor through unprecedented targeting of cysteine 775 and provides the first demonstration that dual cysteine engagement offers superior efficacy over conventional covalent inhibitors by delaying resistance.

  PublisherDOI

• The Hunt Lab Weighs in on Mass Spectrometry–Based Analysis of Protein Posttranslational Modifications

  Molecular & Cellular Proteomics · 2025-03-12 · 1 citations

  reviewOpen access

  Protein posttranslational modifications have traditionally been challenging to identify due to their dynamic regulation and typically low stoichiometry. Methods for phosphopeptide enrichment from complex proteomes developed in the Hunt lab in the late 1990's and early 2000's launched the field of phosphoproteomics, the large-scale analysis of protein phosphorylation sites. To improve phosphopeptide tandem mass spectra and address the further challenge of identifying other labile posttranslational modifications such as glycosylation or tyrosine sulfation, the Hunt lab invented and disseminated electron transfer dissociation, a novel method for peptide and protein fragmentation. Here we provide a brief historical accounting of these discoveries and their ensuing applications.

  PublisherDOI

Recent grants

• NIH Grant R21CA178860

  NIH · $412k · 2015

• (PQ5) Contribution of mitochondrial pathways to metabolic heterogeneity in molecular subtypes of Diffuse Large B Cell Lymphoma

  NIH · $2.8M · 2018–2024

• Novel Screening Platform for Discovery of DUB Targeting Probes

  NIH · $630k · 2019–2023

• NIH Grant R21CA188881

  NIH · $420k · 2018

• Tools for the understudied kinase PNK3

  NIH · $178k · 2019–2020

Frequent coauthors

• Scott B. Ficarro

  Harvard University

  666 shared

• Guillaume Adelmant

  Dana-Farber Cancer Institute

  283 shared

• Nathanael S. Gray

  Dana-Farber Cancer Institute

  256 shared

• Tinghu Zhang

  Stanford University

  122 shared

• Manor Askenazi

  N2 Biomedical (United States)

  87 shared

• Pasi A. Jänne

  74 shared

• Lewis C. Cantley

  Dana-Farber Cancer Institute

  69 shared

• Nicholas Kwiatkowski

  68 shared