About

Dr. Pradipta Ghosh is an Indian-born American physician-scientist, biochemist, and cell biologist with dual expertise in clinical medicine and basic research. She is a Professor in the Departments of Medicine and Cellular & Molecular Medicine at the University of California, San Diego, where she leads an innovative research group focused on cellular communication networks. Her pioneering work has significantly advanced the understanding of how intracellular heterotrimeric G-proteins are regulated by a novel family of guanine-nucleotide exchange modulators (GEMs), independently of traditional G-protein-coupled receptors (GPCRs). This groundbreaking research has uncovered new mechanisms of cell signaling with important implications for chronic diseases such as cancer, fibrosis, immunologic, and metabolic disorders. Ghosh's contributions have provided key insights into how intracellular communication is disrupted in disease, representing a conceptual breakthrough after prior attempts to unravel this network had failed. Recognizing the need for innovative tools to probe the laws governing cellular function, Dr. Ghosh founded the Institute for Network Medicine in 2018. This institute houses four transdisciplinary centers that synergistically work to uncover the unifying principles of cellular behavior, also known as invariants. These centers employ computational approaches, 3D cultures of human organoids and primary cells, advanced cell analysis techniques, and systems engineering to build predictive virtual models that elucidate the emergent properties of invariant cellular functions. Through these efforts, Ghosh aims not only to advance GEM biology but also to test their potential to improve rigor, reproducibility, and precision medicine, thereby reducing the translational gap in drug discovery. Her overarching vision is to harness the complexity of cellular networks to improve human health and engineer smarter systems, paving the way for transformative research and medical advancements. As a physician-scientist, founder of an institute, woman, mother, and mentor, Dr. Ghosh serves as an ideal role model for young scientists. Her lab focuses on the cell biology of signal transduction, particularly the intracellular trimeric-GTPase system modulated by GEMs, which is fundamentally distinct from conventional GPCR signaling. Her group was among the original discoverers of this signaling system, starting with GIV-GEM and extending to other members such as NUCB1/2 and Daple-GEMs. They demonstrated that GEMs serve as vital platforms for intracellular communication networks, coordinating cellular responses and organellar function in response to diverse environmental signals. Using a combination of cell, molecular and structural biology, molecular imaging, systems biology, and bioinformatics, her lab revealed the mechanistic basis of GEM action and its crucial role in coordinating diverse cellular processes. Furthermore, her research has elucidated how aberrations in the GEM system contribute to pathogenic conditions including cancer progression, fibrosis, and insulin resistance, providing impetus for developing drugs targeting GEMs in these and other diseases. Her discoveries highlight that trimeric-GTPase signaling via GEMs is as important, if not more so, than GPCR-mediated signaling for coordinating cellular responses in physiology and for diagnosing and alleviating human suffering.

Research topics

• Biology
• Cell biology
• Medicine
• Computer Science
• Immunology
• Computational biology
• Biochemistry
• Chemistry
• Data science
• Neuroscience
• Pharmacology
• Internal medicine
• Genetics
• Bioinformatics
• Pathology
• Virology

Selected publications

• Abstract 2797: A macrophage endocytic checkpoint for PD-1 governs durable vs hyperprogressive response

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract Clinical responses to PD-1 blockade span a wide continuum, from durable regressions to hyperprogressive disease (HPD); yet the macrophage-intrinsic switches that determine these extremes responses remain undefined. Using a macrophage systems model built from >12,500 transcriptomes and calibrated with single-cell transcriptomes from >1,000 anti-PD-1-treated patients, we identified CCDC88A (encodes the endocytic adaptor, GIV) as a top responder-linked gene and mechanistic driver of tumor-associated macrophage (TAM)states predictive of clinical benefit versus HPD. Loss of GIV in macrophages increased cell-surface PD-1 across species and platforms (primary cell-line, and organoid co-cultures), impaired phagocytosis, and accelerated tumor progression. In syngeneic models, myeloid-specific GIV deletion converted anti-PD-1 therapy from tumor-controlling (beneficial) to tumor-accelerating (hyperprogressive), without altering T cell targeting; transcriptomic analyses of tumor-infiltrating myeloid cells confirmed a shift towards HPD-associated macrophage signatures. Mechanistically, GIV engages a TIR-like BB-loop (TILL) motif within the PD-1 cytoplasmic tail and functions as an endocytic adaptor, driving dynamin-mediated PD-1 internalization and recycling. A pharmacogenomic perturbation strategy revealed that blocking endocytic trafficking phenocopies GIV loss both in vitro and in vivo: PD-1 is trapped on the TAM surface, checkpoint blockade fails, and tumors accelerate under therapy. Conversely, preserving GIV•PD-1 coupling enhances response durability. Finally, we uncover a clinically relevant vulnerability: FDA-approved psychotropic and antiemetic drugs that impair receptor internalization (e.g., prochlorperazine) negate anti-PD-1 efficacy and induce HPD-like progression in vivo, consistent with pharmacoepidemiologic evidence linking such drugs to increased mortality and immune-related adverse events in patients receiving checkpoint therapy. Collectively, these findings establish GIV-dependent PD-1 routing as a macrophage-encoded checkpoint that dictates whether PD-1 blockade elicits tumor clearance or fuels malignant outgrowth. By repositioning TAMs as active arbiters of immunotherapy fate, this work exposes PD-1 trafficking, and its drug-induced derailment, as a new axis for therapeutic control and precision risk mitigation in solid tumors. Citation Format: Madhubanti Mullick, Ella McLaren, Suchismita Roy, Brandon Biagas, Mahitha Anandachar, Vanessa Castillo, Samuel Williams, Celia Espinoza, Courtney Tindle, Gajanan Katkar, Saptarshi Sinha, Pradipta Ghosh. A macrophage endocytic checkpoint for PD-1 governs durable vs hyperprogressive response [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 2797.

  PublisherDOI

• Abstract 4382 Employing a Click-Chemistry-Based Approach to Investigate Protein Targets of Aspirin in Colonic Organoids

  Journal of Biological Chemistry · 2026-05-01

  articleOpen access
  PublisherDOI

• COMPASS: A Web-Based COMPosite Activity Scoring System to Navigate Health and Disease Through Deterministic Digital Biomarkers

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-03 · 1 citations

  articleOpen accessSenior authorCorresponding

  Abstract Quantifying pathway activity in a reproducible and interpretable manner remains a central challenge in systems biology and precision medicine. Here, we introduce COMPASS ( COMP osite A ctivity S coring S ystem), a deterministic, ontology-free, threshold-based framework that converts gene expression into per-sample pathway activity scores without reliance on permutation or reference cohorts. Implemented as an intuitive web application, COMPASS derives gene-specific activation thresholds directly from data, standardizes deviations from these boundaries, and integrates directionally opposing genes into a single composite score using closed-form logic. Implemented as an accessible web application, COMPASS enables users to upload expression matrices, define gene signatures, and perform activity scoring, statistical comparisons, and survival analyses without coding. Across diverse biological and clinical datasets, COMPASS generates stable and transferable digital biomarkers that quantify cellular states, benchmark ‘humanness’ and ‘relevance’ of model systems and enable outcome stratification. In head-to-head comparisons with widely used single-sample enrichment methods (GSVA and ssGSEA), COMPASS shows consistent performance across multi-cohort datasets, with improved discrimination when integrating bidirectional gene programs. Stratified bootstrap analyses further demonstrate reduced variability and increased robustness. By directly linking expression thresholds, deviation, and gene directionality, COMPASS provides a transparent and generalizable framework for ontology-free pathway activity quantification and outcome modeling. Impact statement COMPASS redefines pathway analysis by replacing permutation-based enrichment with a closed-form, threshold-driven framework that yields robust, interpretable, and clinically actionable activity scores, enabling reproducible, sample-level pathway scoring without coding and bridging gene expression to clinically meaningful outcomes.

  PublisherOA PDFDOI

• Distinct Colitis-Associated Macrophages Drive NOD2-Dependent Bacterial Sensing and Gut Homeostasis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-24 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Single-cell studies have revealed that intestinal macrophages maintain gut homeostasis through the balanced actions of reactive (inflammatory) and tolerant (non-inflammatory) subpopulations. How such balance is impaired in inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), remains unresolved. Here, we define colon-specific macrophage states and reveal the critical role of n on- i nflammatory c olon- a ssociated m acrophages (niColAMs) in IBD recovery. Through trans-scale analyses—integrating computational transcriptomics, proteomics, and in vivo interventional studies—we identified GIV ( CCDC88A ) as a key regulator of niColAMs. GIV emerged as the top-ranked gene in niColAMs that physically and functionally interacts with NOD2, an innate immune sensor implicated in CD and UC. Myeloid-specific GIV depletion exacerbates infectious colitis, prolongs disease, and abolishes the protective effects of the NOD2 ligand, muramyl dipeptide, in colitis and sepsis models. Mechanistically, GIV’s C-terminus binds the terminal leucine-rich repeat (LRR#10) of NOD2 and is required for NOD2 to dampen inflammation and clear microbes. The CD-associated 1007fs NOD2-variant, which lacks LRR#10, cannot bind GIV—providing critical insights into how this clinically relevant variant impairs microbial sensing and clearance. These findings illuminate a critical GIV-NOD2 axis essential for gut homeostasis and highlight its disruption as a driver of dysbiosis and inflammation in IBD.

  PublisherDOI

• Distinct colitis-associated macrophages drive NOD2-dependent bacterial sensing and gut homeostasis

  Journal of Clinical Investigation · 2025-10-02 · 4 citations

  articleOpen accessSenior author

  Single-cell studies have revealed that intestinal macrophages maintain gut homeostasis through the balanced actions of reactive (inflammatory) and tolerant (noninflammatory) subpopulations. How such balance is impaired in inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), remains unresolved. Here, we define colon-specific macrophage states and reveal the critical role of noninflammatory colon-associated macrophages (niColAMs) in IBD recovery. Through trans-scale analyses-integrating computational transcriptomics, proteomics, and in vivo interventional studies-we identified GIV (CCDC88A) as a key regulator of niColAMs. GIV emerged as the top-ranked gene in niColAMs that physically and functionally interacts with NOD2, an innate immune sensor implicated in CD and UC. Myeloid-specific GIV depletion exacerbates infectious colitis, prolongs disease, and abolishes the protective effects of the NOD2 ligand muramyl dipeptide in colitis and sepsis models. Mechanistically, GIV's C-terminus binds the terminal leucine-rich repeat 10 (LRR 10) of NOD2 and is required for NOD2 to dampen inflammation and clear microbes. The CD-associated 1007fs NOD2 variant, which lacks LRR 10, cannot bind GIV, which provides critical insights into how this clinically relevant variant impairs microbial sensing and clearance. These findings illuminate a critical GIV•NOD2 axis essential for gut homeostasis and highlight its disruption as a driver of dysbiosis and inflammation in IBD.

  PublisherOA PDFDOI

• Abstract 4363113: A Systems Biology–Driven Strategy to ‘Defat’ Lipid-Associated Macrophages and Reverse Atherosclerosis

  Circulation · 2025-11-03

  articleSenior author

  Introduction: Current atherosclerosis therapies like statins lower LDL cholesterol, but they do not reverse established plaques. Even with aggressive LDL-lowering, residual risk persists, driven in part by immunologic factors. A key player in these processes is lipid-associated macrophages (LAM), which accumulate lipids and drive inflammation and plaque instability. Despite their central role, LAM remain un-targetable and here we tackle their untapped therapeutic potential. Methods: We used a systems biology–driven network transcriptomics approach to identify key myeloid modulators of atherosclerosis. Computational analyses identified CCDC88A , which encodes the cAMP-inhibitor GIV, as a proatherogenic factor. This finding was validated by in vivo and in vitro studies. Our study includes two mouse models: myeloid-specific GIV knockout ( Mac GIV-KO) and ApoE-deficient Mac GIV-KO (n = 8–15, both sexes). Mice were on a Western diet for 12 wks; aortic plaque burden was assessed using Oil Red O staining. For in vitro study, murine peritoneal and THP1-derived macrophages were treated with oxLDL to assess LAM formation, cholesterol uptake/efflux and lipolysis. RNA-seq was used to identify genes in cholesterol metabolism and efflux. Translational relevance was assessed using human PBMCs and a small-molecule inhibitor targeting the GIV/cAMP pathway. Results: Compared to WT and ApoE-KO controls, GIV-KO reduces aortic plaque burden by 70% and 40%, respectively. Macrophage GIV deficiency inhibits LAM formation, increases cholesterol efflux and basal lipolysis, and is associated with increased mRNA expression of the ‘gatekeeper’ of reverse cholesterol transport (RCT) from peripheral tissues ( Abca1 ) and its transcriptional regulators (LXRα/β). Mechanistically, GIV activates Gαi/βγ proteins and inhibits a well-established anti-atherogenic cyclic AMP (cAMP). GIV binds and sequesters ABCA1 on the endomembrane, suppressing cholesterol efflux. GIV-KO raises cAMP levels, positions ABCA1 at the cell surface and unleashes its activity via a 2-pronged mechanism—both converging on the GIV/cAMP axis: (1) transcriptional activation (CREB), and (2) post-translational modulation via PKA. Small-molecule inhibitors of the GIV/cAMP axis reverse LAMs in both murine and human macrophages, where statins and β-blockers fail. Conclusion: This study reveals a therapeutic strategy to augment RCT via ABCA1, ‘defat’ LAM and regress plaques, offering a novel approach to treat advanced atherosclerosis.

  PublisherDOI

• ASO Visual Abstract: Bright and Specific Targeting of Metastatic Lymph Nodes in Orthotopic Mouse Models of Gastric Cancer with a Fluorescent Anti-CEA Antibody

  Annals of Surgical Oncology · 2025-03-10

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  PublisherDOI

• Robust method for surface modulation in Cu-Zn alloys via pulsed laser surface melting

  Vacuum · 2025-09-16

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• 1216: A LIVING ORGANOID BIOBANK OF CROHN’S DISEASE PATIENTS REVEALS DISTINCT CLINICAL CORRELATES OF MOLECULAR SUBYTPES OF DISEASE

  Gastroenterology · 2025-05-01

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• A new locoregional mouse model of gastric cancer for identifying probes for fluorescence guided surgery

  Surgery · 2025-03-04 · 4 citations

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Recent grants

• Integrators of Metastatic Potential

  NIH · $2.3M · 2019–2026

• Modulation of Macrophage Polarization by Heterotrimeric G proteins: Implications of Gastrointestinal Inflammation

  NIH · $3.2M · 2019–2031

• Precision therapeutics of inflammatory bowel disease guided by Boolean logic

  NIH · $937k · 2020–2023

• NIH Grant R01CA160911

  NIH · $1.8M · 2020

• Spatial Regulation of RGS and G Protein Signaling

  NIH · $6.9M · 2003–2022

Frequent coauthors

• Debashis Sahoo

  University of California, San Diego

  122 shared

• Amer Ali Abd El‐Hafeez

  Children Cancer Hospital

  82 shared

• Soumita Das

  University of Massachusetts Lowell

  78 shared

• Jason Ear

  California State Polytechnic University

  49 shared

• Ibrahim M. Sayed

  University of Massachusetts Lowell

  40 shared

• Nicolas Aznar

  Centre National de la Recherche Scientifique

  40 shared

• Gajanan D. Katkar

  University of California, San Diego

  38 shared

• Saptarshi Sinha

  University of California, San Diego

  35 shared