About

Professor Jacob Geri is the leader of the Geri Lab at Weill Cornell Medicine, where the focus is on discovering disease-relevant protein-biomolecule interactions through the invention and application of new proximity labeling technologies. His lab's work is highly interdisciplinary and collaborative, combining methods in organic synthesis, photocatalysis, molecular biology, optical control, ion mobility mass spectrometry, and proteomics to explore biological questions that cannot be addressed with existing methods. The long-term goal of his research is to utilize the obtained information about protein interactions to identify novel therapeutic strategies.

Research topics

• Chemistry
• Biochemistry
• Computational biology
• Biology
• Materials science
• Combinatorial chemistry
• Biophysics
• Nanotechnology
• Genetics
• Botany
• Cell biology
• Photochemistry

Selected publications

• SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities

  Cancer Discovery · 2026-04-21

  article

  Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCL derive from follicular B cells engaged in adaptive immune responses. By studying co-occurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extra-follicular trajectory. Using animal models and human specimens, we find this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory and a distinct, autoimmune B-cell-like state. This trajectory is associated with sex-biased outcomes: female patients and mice exhibit reduced survival compared to males in our cohorts. Further analysis links this disparity to enhanced X-chromosome-linked expression and functionality of toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.

  PublisherDOI

• Proteomic Profiling of Human Extracellular Vesicles Reveals Diagnostic Biomarkers for Colon Adenocarcinoma

  Journal of Extracellular Vesicles · 2026-04-01

  articleOpen access

  Early detection of colon adenocarcinoma (COAD) remains suboptimal. Fecal tests fail to diagnose 30% of stage I cancer, and serum CEA lacks sensitivity (< 40%). Extracellular vesicles (EVs) circulate systemically and package tumor-related cargo, making them attractive non-invasive biomarkers for cancer diagnosis. We profiled the EV proteome from 233 human patients using LC-MS/MS, including stage I‑IV tumors with matched non‑tumor colon tissues (n = 50 each; n = 100), paired pre‑/post‑operative plasma (n = 90) and healthy plasma (n = 43). Circulating EVs contained both tumor-specific and stromal/immune cell-derived proteins, reflecting the systemic nature of EV biology in the cancer setting. Proteomic analysis identified 745 proteins enriched in tumor-derived EVs (e.g., SRPK1, THBS2) and 127 proteins enriched in adjacent tissues. Plasma EVs revealed 166 proteins enriched in COAD (e.g., UBA1, FCN1) and 233 enriched in healthy controls. Pathway analysis linked tumor EV cargo to angiogenesis, mRNA splicing, TGF‑β signalling and RNA translation. Notably, a cross-cancer comparison (pancreatic = 10, lung = 14 cases) revealed that 76% of tumor EV proteins were COAD-specific, highlighting tissue of origin specificity. We further developed a 10-protein EV panel comprising seven tumor-associated and three healthy-enriched EV proteins, which effectively distinguished COAD patients from healthy controls in the two validation cohorts (n = 104 and n = 215), achieving > 90% sensitivity for differentiating COAD from healthy and non-COAD colorectal conditions. Six weeks after curative resection, tumor-associated EV proteins decreased by > 70%, whereas healthy-associated proteins rebounded to baseline, indicating surgical responsiveness. Collectively, EV protein signatures provide a sensitive and tissue-specific window into tumor-host communication, further supporting blood-based early detection of COAD.

  PublisherDOI

• Abstract NG10: First-in-class dual AR/AR-V7 molecular glue degraders targeting the undruggable N-terminal domain to overcome therapeutic resistance in prostate cancer

  Cancer Research · 2026-04-17

  article

  Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains a uniformly lethal malignancy, driven by persistent dependence on the androgen receptor (AR) signaling pathway. Over 90% of prostate cancer (PC) therapies target the AR ligand-binding domain (LBD). However, the selective pressure imposed by these agents inevitably promotes therapeutic resistance and disease progression, ultimately driving mortality. Expression of AR splice variants, most notably AR-V7, that lack the LBD yet remain constitutively active, is a key mechanism of treatment resistance. Clinically, AR-V7 expression is strongly associated with resistance to all AR pathway inhibitors (ARPIs), including enzalutamide and abiraterone. Alarmingly, AR-V7 is detected in &amp;gt;75% of men with mCRPC, yet there are no approved inhibitors—underscoring a profound unmet clinical need. Thus, directly targeting AR-V7 represents one of the most urgent and unsolved challenges in prostate cancer drug development, with clear implications for survival and quality of life. To address this challenge, we conducted a high-throughput phenotypic screen of 170,000 small molecules and identified a novel hit compound—the first-in-class dual degrader of AR-V7 and full-length AR, defined by a previously unreported chemotype. Medicinal chemistry/SAR optimization yielded potent lead compounds (IC50 &amp;lt;10 nM) with improved selectivity and favorable drug-like properties. This systematic optimization effort combined iterative analog synthesis, structure-activity analysis, and physicochemical profiling to deliver nanomolar potency alongside favorable solubility and stability profiles, enabling downstream in vivo evaluation. In vivo, pharmacokinetic (PK)-optimized compounds significantly suppressed tumor growth in the enzalutamide-resistant 22Rv1 xenograft model, reversed resistance, and outperformed ARV-110, the only full-length AR-PROTAC degrader in clinical trials, by &amp;gt;10-fold in efficacy, with no effect on mouse body weight—establishing both robust antitumor activity and excellent tolerability. Pharmacodynamic (PD) studies revealed near-complete degradation of AR/AR-V7 proteins within 24 hours of final dose, tightly correlating with rapid tumor growth inhibition. Importantly, toxicity studies across multiple dosing regimens showed no histopathological abnormalities in major organs, further supporting the translational potential of this new therapeutic class. Mechanistic studies confirmed rapid degradation of AR-V7/AR via the ubiquitin-proteasome pathway, dependent on Cullin-RING E3 ligase activity. A CRISPR-based E3 ligase screen implicated the DDB1-RBX1-Cullin-RING complex as the mediator of degradation, consistent with a molecular glue mechanism. This represents one of the first demonstrations of a molecular glue-mediated engagement of this E3 ligase complex in prostate cancer, further underscoring the novelty of our approach. Global proteomics demonstrated deep proteome coverage of the entire proteome of ∼10,000 proteins and exceptional selectivity: AR/AR-V7 ranked among the top 1% of significantly downregulated proteins, while sparing all other major human nuclear receptors, including ER, PR, and GR, and avoiding liabilities of prior PROTAC-based AR degraders—highlighting strong specificity and favorable translational potential for clinical development. Using cellular thermal shift assays, AR truncation mutants, and Cryo-EM studies, we demonstrated direct binding of our lead compounds to the intrinsically disordered N-terminal domain (NTD), shared by both AR and AR-V7. We further mapped the binding site to the TAU1/AF-1 subdomain— the first demonstration of small-molecule engagement of this notoriously “undruggable” region. This provides long-sought proof-of-concept that the unstructured AR-NTD, which has defied decades of drug targeting efforts, can indeed be targeted with small molecules. Our findings therefore expand the druggable proteome to include intrinsically disordered regions, with broad implications beyond prostate cancer. Importantly, our lead compounds were able to overcome enzalutamide resistance and inhibit all clinically validated ARPIs-resistant isoforms, including LBD-domain mutations. These results suggest that our compounds deliver not only a solution for AR-V7-mediated resistance but also a generalized “resistance-proof” strategy by simultaneously targeting multiple clinically relevant AR variants. Taken together, these data establish our lead compounds as first-in-class dual AR-V7/AR molecular glue degraders with a novel NTD-targeted mechanism and strong preclinical activity. To advance toward clinical translation, the next phase of our research will systematically define the structural basis of compound-NTD interaction, evaluate drug metabolism and safety in higher-order animal models, and explore rational combination strategies with standard-of-care agents. The objective here is to define the precise molecular mechanism of action and assess therapeutic potential in clinically relevant models. Collectively, these findings support a paradigm-shifting therapeutic strategy for targeting previously “undruggable” drivers like AR-V7. Unlike all existing AR-directed therapies that target the LBD, this approach simultaneously degrades AR and AR-V7 in a single treatment, directly addressing the central clinical challenge of therapeutic resistance. Moreover, by establishing proof-of-concept for disordered protein domain-targeted glue degraders, this work opens a broadly applicable platform to drug other transcription factors and intrinsically disordered proteins implicated across multiple cancers and diseases. By enabling dual degradation of AR (the initiating oncogenic driver in PC) and AR-V7 (the lethal, treatment-resistant variant), our drug candidate has the potential to transform the treatment landscape—benefiting patients with both hormone-sensitive and advanced castration-resistant disease, while delaying or preventing AR-V7-mediated progression. Ultimately, this work charts a new course for prostate cancer therapy by providing a first-in-class approach capable of addressing the major cause of therapeutic failure, with the potential to meaningfully extend survival and improve quality of life. Citation Format: CheukMan Cherie Au, Michelle Naidoo, Catrina Estrella, Kiran Kumari Sahu, Charles D. Warren, Prerna Vatsa, Ying Wang, Zhao Wang, David M. Nanus, Urko del Castillo, Jacob B. Geri, Paraskevi Giannakakou. First-in-class dual AR/AR-V7 molecular glue degraders targeting the undruggable N-terminal domain to overcome therapeutic resistance in prostate 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 NG10.

  PublisherDOI

• MassIVE MSV000101185 - Spatial Protein Interactomics in Solid Primary Human Tissue

  UC San Diego · 2026-01-01

  datasetOpen access1st authorCorresponding
  PublisherDOI

• MassIVE MSV000101925 - Dataset for Carbocation Based Proximity Labeling

  UC San Diego · 2026-01-01

  datasetOpen access1st authorCorresponding
  PublisherDOI

• Abstract 6524: Identification of diagnostic and prognostic extracellular vesicle biomarker signatures in inflammatory breast cancer

  Cancer Research · 2026-04-03

  article

  Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive type of BC with a very poor prognosis and accounts for 10% of BC-related deaths. Diagnosis of IBC is particularly challenging, as its symptoms resemble mammary infection and the tumor often presents with metastases at the time of diagnosis. Despite growing body of work, tools for identification and risk stratification of patients with IBC are lacking. Small extracellular vesicles (sEVs) mediate cell-to-cell communication and are released in the blood circulation, thus potentially serving as predictive and prognostic biomarkers. We have previously shown that sEVs are functional determinants of BC progression, but their role in IBC outcomes is not known. Methods: sEVs were isolated from longitudinal plasma samples collected from patients with IBC (n=20), matched non-IBC patients (n=11), and healthy controls (HC, n=15) by ultracentrifugation and liquid chromatography mass spectrometry. Statistical analyses were conducted in R: (a) Kruskal-Wallis tests, followed by pairwise Wilcoxon rank-sum tests with Benjamini-Hochberg false-discovery rate (FDR) correction (IBC vs. non-IBC and HC); (b) Spearman's correlation with FDR correction for multiple testing (association with clinical parameters); (c) receiver operating characteristic (ROC) curve analysis (diagnostic performance); (d) Kaplan-Meier survival analysis with log-rank testing and Cox proportional hazards regression (association with overall survival [OS]). Results: Out of the 2540 sEV proteins detected, we have identified a signature of 20+ proteins enriched more than 2-fold in plasma sEVs from IBC patients compared to non-IBC or HC and associated with immune response pathways. In univariate analysis, a total of 10 sEV biomarkers achieved an area under the curve (AUC) &amp;gt; 0.88, including MARCKSL1, which demonstrated the highest discriminatory power for IBC vs. non-IBC (AUC = 0.955, confidence interval [CI]: 0.878-1.000, sensitivity 100%, specificity 81.8%). When sEV proteins were compared with clinicopathological features, 998 significant associations were identified (FDR &amp;lt; 0.05 and p-value &amp;lt; 0.05), with the strongest associations observed for Ki67 proliferation index, tumor grading, and OS. Exploratory survival analyses identified a set of 20+ overrepresented sEV proteins in patients with IBC and worse OS. High composite scores of the top three sEV biomarkers (correlation &amp;gt; 0.81, p &amp;lt; 0.0001) showed a trend toward increased mortality with good prognostic discrimination (C-index = 0.705). Conclusions: Our comprehensive proteomic analysis revealed extensive and robust associations between circulating sEV protein biomarkers, IBC detection, and clinical parameters, suggesting potential clinical utility as “liquid biopsy” biomarkers for IBC diagnosis and prognosis. Further validation in larger independent cohorts is warranted. Citation Format: Serena Lucotti, Mara Serena Serafini, Eleonora Nicolò, Letizia Pontolillo, Charles Warren, Brenno Pastò, Caterina Gianni, Nadia Bayou, Jacob B. Geri, Carolina Reduzzi, Massimo Cristofanilli, David Lyden. Identification of diagnostic and prognostic extracellular vesicle biomarker signatures in inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6524.

  PublisherDOI

• μMap-FFPE: A High-Resolution Protein Proximity Labeling Platform for Formalin-Fixed Paraffin-Embedded Tissue Samples

  Journal of the American Chemical Society · 2025-06-26 · 8 citations

  article

  Many disease states can be understood by elucidating small-scale biomolecular protein interaction networks, or microenvironments. Photoproximity labeling methods, like μMap, have recently emerged as high-resolution techniques for mapping spatial relationships within subcellular architectures. However, in vitro models typically utilized lack the cell-type heterogeneity and three-dimensional structure essential for translating findings to clinical settings. To this end, formalin-fixed paraffin-embedded (FFPE) tissues are invaluable model systems for biomedical research, as they preserve complex multicellular interaction networks in their natural environment. While identifying microscale interactions in these samples could provide critical clinical insights, chemical modifications introduced during formalin-fixation and de-cross-linking are incompatible with standard photoproximity labeling techniques. Herein, we introduce μMap-FFPE, a new labeling system that enables comparison of the CD20 interactome across healthy cells, cancerous cells, and preserved patient tissues.

  PublisherDOI

• Deletion of the transcription factor ATF4 in a model of clear cell renal cell carcinoma

  Neoplasia · 2025-06-04 · 1 citations

  articleOpen access

  Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults. We generated TRAnsgenic of Cancer of the Kidney (TRACK) mice that express a triple-mutant (P402A, P564A, and N803A) human HIF1α construct specifically in their proximal tubule (PT) cells. We demonstrated that the elevated lipid content found in human ccRCCs is mimicked in these TRACK PT cells. Additionally, we reported that ATF4 (activating transcription factor 4), a transcription factor, and its target genes were highly expressed both in human ccRCCs and in TRACK PT cells. To delineate the functions of ATF4 in ccRCC we have now generated TRACK mice in which the ATF4 gene is specifically deleted in PT cells (GCREA∆T). Our genome-wide transcriptomics and proteomics studies show that expression of ∼20 % of mRNAs and proteins is significantly altered in GCREA∆T compared to TRACK kidney cortices. Gene set enrichment analyses (GSEAs) of mRNAs demonstrate that the fatty acid metabolism pathway is upregulated in TRACK vs WT and that, conversely, ATF4 deletion reduces mRNAs in the fatty acid metabolism pathway (e.g., ATP citrate lyase). Moreover, some transcripts elevated in human ccRCC are reduced in GCREA∆T vs. TRACK kidney cortices and cystic, pre-cancerous lesions are also reduced. Thus, ATF4 actions increase both lipid droplet accumulation in this ccRCC model and oncogenesis-related gene expression. These data suggest that ATF4 contributes to the formation of ccRCC tumors and may be a potential therapeutic target.

  PublisherDOI

• The critical role of PSAC channel in malaria parasite survival is driven home by phenotypic screening under relevant nutrient levels

  Cell chemical biology · 2025-05-23 · 3 citations

  articleOpen access

  Spreading resistance to front-line treatments necessitate the search for new classes of antimalarials. Limitations of standard screening conditions lead us to develop an assay using culture media that more closely reflects nutrient levels in human serum to reveal new therapeutically relevant parasite pathways. Our approach was validated by testing 22k compounds followed by a full 750k compound screen and identified 29 chemotypes with higher activity in nutrient restricted media that were further characterized. Through a combination of chemo-genomics and innovative photocatalytic proximity labeling proteomics, we identified the target of two compounds as the CLAG3 component of the plasmodial surface anion channel (PSAC). Strikingly, every one of the other 29 chemotypes selected was also found to block PSAC activity, highlighting the importance of this nutrient channel for parasite survival under physiological conditions. The effect of PSAC inhibitors in the in vivo humanized mouse model was confirmed.

  PublisherDOI

• Retinoic acid receptor β deletion in podocytes causes kidney and liver dysfunction, modeling nephrotic syndrome

  Journal of Molecular Endocrinology · 2025-12-09

  articleOpen access

  Differentially altered expression of transcripts of retinoic acid receptors α, β, γ (Rarα, β, γ), which mediate the actions of all-trans retinoic acid (RA), is observed in glomeruli of nephrotic syndrome (NS) patients vs normal individuals, with Rarβ reduced and both RARα and RARγ increased. Thus, we generated a mouse model (PCRB) with Rarβ specifically deleted in podocytes to define the glomerular actions of Rarβ. Rarβ deletion in PCRB mice results in podocyte loss, podocyte foot process effacement, glomerular basement membrane (GBM) thickening, reduced podocyte adhesion to the GBM, lipid accumulation in glomeruli, and hyperfiltration leading to albuminuria. Genome-wide transcriptomics and proteomics studies of glomeruli revealed that Rarβ deletion increased Mogat, Dgat, and Hmgcs mRNAs, which catalyze triglyceride and cholesterol synthesis, and Slc27a2 and Cd36, which mediate fatty acid uptake, recapitulating NS symptoms. Surprisingly, podocyte-specific Rarβ deletion also increased key mRNAs and proteins involved in fatty acid uptake and lipid biosynthesis in the liver, promoting steatohepatitis and systemic hyperlipidemia. These data indicate that Rarβ signaling in the kidney has a profound impact on both kidney and liver functions and suggest that Rarβ plays an important role in regulating kidney-liver crosstalk. PCRB mice may be a useful model of NS.

  PublisherDOI

Recent grants

• Photoredox-Enabled Applications of Primary Amines as Alkylating Reagents

  NIH · $123k · 2019–2022

Frequent coauthors

• Nathaniel K. Szymczak

  University of Michigan–Ann Arbor

  29 shared

• Manabu Nagayama

  Jichi Medical University

  15 shared

• Randy Longman

  Cornell University

  15 shared

• Charles Ng

  New York Hospital Queens

  15 shared

• Irina Matei

  Cornell University

  9 shared

• Padma P. Nanaware

  Cornell University

  9 shared

• David Lyden

  Children's Cancer and Blood Foundation

  9 shared

• Laura Santambrogio

  9 shared

Education

• PhD, Chemistry

  University of Michigan

  2018