Biology subjects

Mullick, M.

Publications and source records attributed to Mullick, M..

7 recordsLinked to original sources

bioRxiv2026

Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease

Inflammatory bowel diseases (IBD) remain a relapsing, treatment-refractory disorder marked by progressive tissue injury and inflammation despite expanding immune-targeted therapies. We established a prospective cohort integrating stromal biobanking, functional phenotyping, cross-cohort benchmarking, and outcome modeling to define disease-anchored cellular states. Colonic myofibroblasts from 34 individuals spanning health, ulcerative colitis, and Crohns disease resolved into two dominant states: inflammatory (IMFs) and quiescent (QMFs) myofibroblasts. QMF predominance forecasted remission, whereas IMF predominance increased the odds of worsening endoscopic severity despite therapy escalation during follow-up by [~]4.6-fold, linking early stromal biology to clinical outcomes. Unlike QMFs, IMFs exhibited a senescence-associated secretory phenotype that impaired epithelial stemness, barrier integrity, and innate immune fitness. State-guided prioritization identified EDNRB-antagonism as a high-confidence stromal intervention, reversing pathogenic phenotypes across orthogonal assays and species. Outcome simulation positioned stromal-state reversibility by EDNRB-antagonism as a precision axis, reducing odds of recalcitrance by [~]96.4% and reframing treatment resistance as a reversible stromal state. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/720931v2_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@3b2c50org.highwire.dtl.DTLVardef@da5400org.highwire.dtl.DTLVardef@1c100c1org.highwire.dtl.DTLVardef@1882e1_HPS_FORMAT_FIGEXP M_FIG C_FIG In this work, Tindle et al. identify reversible stromal states that govern remission vs. recalcitrant outcomes in IBD and nominate precision reprogramming of pathogenic myofibroblasts as a new therapeutic strategy.

physiology↗

bioRxiv2026

An Endocytic Checkpoint Controls Macrophage PD-1 Function and Immunotherapy Fate

Responses to PD1 blockade span durable tumor control to hyperprogressive disease (HPD), yet innate immune mechanisms governing these extremes remain undefined. Here we integrate a macrophage systems atlas (>12,500 transcriptomes) with single-cell profiles from >1,000 anti-PD1 treated patients, to identify CCDC88A (GIV) as a macrophage-intrinsic determinant of durable response versus HPD. GIV loss increases PD1 surface retention, suppresses phagocytosis, and accelerates tumor growth across murine models, human macrophages, and patient-derived organoids. Myeloid-specific GIV deletion converts PD1 blockade from tumor-restraining to tumor-accelerating by reprogramming macrophages toward HPD-like states. Mechanistically, GIV engages a conserved TIR-like [TILL] motif within the PD1 cytoplasmic tail to drive dynamin-dependent endocytosis, coupling innate immune signaling logic to checkpoint receptor trafficking. Pharmacologic disruption of this axis phenocopies GIV loss, revealing an endocytic vulnerability that undermines checkpoint efficacy and triggers accelerated growth at relapse. These findings define PD1 routing, rather than ligand-binding, as a macrophage-encoded checkpoint governing antitumor immunity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/718292v1_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@a8f83aorg.highwire.dtl.DTLVardef@140dc7dorg.highwire.dtl.DTLVardef@14bc366org.highwire.dtl.DTLVardef@1096b8a_HPS_FORMAT_FIGEXP M_FIG GRAPHIC ABSTRACT C_FIG In briefMullick et al. show that PD1 trafficking in tumor associated macrophages (TAMs), controlled by the endocytic adaptor GIV/Girdin, determines the durability of immunotherapy. Disrupting this pathway traps PD1 at the surface, converts checkpoint blockade into hyperprogressive disease, and abolishes therapeutic benefit, revealing PD1 routing as a macrophage-encoded checkpoint of immunotherapy outcome. HighlightsO_LIGIV defines macrophage states that stratify durable response vs hyperprogressive disease C_LIO_LIGIV limits surface checkpoint accumulation by facilitating PD1 endocytosis C_LIO_LILoss of GIV traps PD1 at the membrane and drives hyperprogressive disease C_LIO_LIEndocytic blockade phenocopies GIV loss and abolishes checkpoint efficacy C_LIO_LIPsychotropic drugs disrupt PD1 trafficking and accelerate tumor growth C_LI

cancer biology↗

bioRxiv2026

A NOD2-Encoded Toggle Switch Resolves the Host-Microbe Battle Over Cyclic AMP Control

Pathogens hijack macrophages by triggering pathological cAMP surges that block phagolysosomal killing--a defect mirrored in phagocytes from refractory colitis. We identify a host-encoded, pathogen-specific surge-protector comprised of a three-protein toggle: The innate sensor NOD2 binds and masks an evolutionarily conserved motif in GIV that activates trimeric-GTPase Gi, enforcing a biphasic surge-to-plunge cAMP-program: early, NOD2*GIV assembly permits a brief, tolerogenic cAMP rise, whereas subsequent GIV*Gi engagement collapses cAMP to drive phagolysosomal fusion and microbial clearance. Structural, biochemical, and ultrastructural analyses reveal how molecular toggling imposes precise spatial and temporal control. Pharmacogenomic perturbations pinpoint cAMP-PKA hyperactivation as the defining lesion in GIV-deficient macrophages. Functional studies in primary macrophages and human gut organoid co-cultures show that toggling the NOD2*GIV*Gi-axis is necessary and sufficient to convert tolerant macrophages into microbicidal machines that preserve mucosal barrier integrity. These findings uncover a druggable cAMP-control pathway with therapeutic promise in colitis. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/715116v1_ufig1.gif" ALT="Figure 1"> View larger version (70K): org.highwire.dtl.DTLVardef@53cd40org.highwire.dtl.DTLVardef@1c83c82org.highwire.dtl.DTLVardef@fcbc58org.highwire.dtl.DTLVardef@b14f8e_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC BlurbPathogens hijack macrophages by inducing cAMP surges that help them evade clearance. Anandachar et al. identify a host "toggle switch" in which NOD2 and G proteins compete for GIV, driving a rapid and robust surge-to-plunge transition in cAMP. This temporal switch limits tolerogenic signaling, restores microbial clearance and barrier integrity, and unveils a targetable host pathway in infection and IBD. HighlightsO_LIPathogens exploit cAMP surges in macrophages to block phagolysosomal killing of microbes C_LIO_LIGIV acts as a molecular "toggle" linking NOD2 sensing to Gi-mediated cAMP control C_LIO_LIStructural and mutagenesis studies reveal mutually exclusive binding of NOD2 and Gi to GIV C_LIO_LIPharmacogenomic perturbations pinpoint PKA, not EPAC, as the critical downstream effector C_LIO_LIOrganoid co-cultures show NOD2-GIV-PKA crosstalk safeguards microbial clearance and gut barrier integrity C_LI

immunology↗

bioRxiv2026

A Druggable G Protein Checkpoint in Cholesterol Efflux

Immunometabolic diseases such as obesity, fatty liver, and atherosclerosis arise when lipid-associated macrophages (LAMs) fail to resolve lipid overload via reverse cholesterol transport (RCT), the bodys sole pathway for lipid disposal. How RCT is restrained in disease remains unknown. Integrating systems modeling with human plaque transcriptomes, we identify LAM subpopulations associated with plaque progression and uncover CCDC88A (GIV) as a macrophage-intrinsic checkpoint on RCT. Myeloid-specific GIV deletion in mice reduces aortic plaque burden, mobilizes hepatic and adipose lipid stores and promotes fecal sterol disposal. Mechanistically, GIV sequesters the cholesterol transporter ABCA1 within endomembranes and activates Gi[bullet]{beta}{gamma} signaling to suppress cAMP/PKA-CREB-dependent efflux programs. Pharmacogenomic disruption of this checkpoint reactivates efflux programs. In human plaque-in-a-dish models targeting this pathway restored efflux where statins and {beta}-blockers failed, translating to an estimated [~]98% reduction in plaque-progression risk in outcome modeling. Thus, RCT-restoration represents a macrophage-intrinsic therapeutic paradigm for immunometabolic disease. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/705962v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@50dd10org.highwire.dtl.DTLVardef@e16d9borg.highwire.dtl.DTLVardef@1e2eaf3org.highwire.dtl.DTLVardef@af29b9_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC blurbLipid-associated macrophages drive immunometabolic disease. Katkar et al. show that disabling a GIV-dependent G-protein brake restores cholesterol efflux, reverses plaque lipid accumulation, and establishes reverse cholesterol transport as a druggable therapeutic axis. HighlightsO_LIStatins slow but rarely reverse plaque burden, leaving residual risk driven by LAM dysfunction C_LIO_LIGIV (CCDC88A) non-canonically modulates Gi to suppress macrophage cholesterol efflux C_LIO_LIGIV loss or inhibition restores ABCA1 activity via transcriptional and post-translational control C_LIO_LIBlocking GIV[bullet]Gi checkpoint defats LAMs, regresses plaques, and relieves systemic lipid overload C_LIO_LISIdentifies a druggable node that redefines RCT restoration as a therapeutic paradigm in immunometabolic disease C_LI

immunology↗

bioRxiv2025

Distinct Colitis-Associated Macrophages Drive NOD2-DependentBacterial Sensing and Gut Homeostasis

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 Crohns disease (CD) and ulcerative colitis (UC), remains unresolved. Here, we define colon-specific macrophage states and reveal the critical role of non-inflammatory 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, GIVs 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.

immunology↗

bioRxiv2024

Logical Network Perturbations Guide Precise Target Prioritization for Drug Development

Despite advances in artificial intelligence (AI), target-based drug development remains costly, complex, and imprecise. We introduce F.O.R.W.A.R.D [Framework for Outcome-based Research and Drug Development], a network-based target prioritization platform, and demonstrate its utility in the challenging landscape of Inflammatory Bowel Diseases (IBD), a chronic, multifactorial condition. F.O.R.W.A.R.D uses real-world clinical outcomes, and a machine-learning classifier trained on transcriptomic data from seven prospective randomized trials across four drugs. It defines remission at the molecular level and calculates, using network connectivity, the likelihood that targeting a given molecule will induce remission-associated gene expression. Benchmarking against 210 completed trials across 52 targets, F.O.R.W.A.R.D achieved 100% predictive accuracy--despite variability in drug mechanisms and trial designs. Single-cell RNA-seq and a prospective biobank of patient-derived organoids confirmed that the remission signature is epithelium-specific and tracks with poor outcomes. F.O.R.W.A.R.D enables in-silico phase zero trials to inform trial design, revive shelved drugs, and guide early termination decisions. Broadly applicable and iteratively refined by emerging trial data, F.O.R.W.A.R.D has the potential to reshape drug discovery--bringing foresight to hindsight, and empowering both R&D and human-in-the-loop clinical decision-making.

bioinformatics↗

bioRxiv2022

Coupling of NOD2 to GIV is Required for Bacterial Sensing

ABSTRACT/SUMMARYSensing of pathogens by Nucleotide oligomerization domain (NOD)-like 2 receptor (NOD2) induces a protective inflammatory response that coordinates bacterial clearance. Polymorphisms in NOD2 impair bacterial clearance, leading to chronic gut inflammation in Crohns disease (CD) via mechanisms that remain incompletely understood. We identify GIV/Girdin (CCDC88A) as a NOD2-interactor that shapes bacterial sensing-and-signaling in macrophages. Myeloid-specific GIV depletion exacerbated and protracted infectious colitis and abolished the protective effect of muramyl dipeptide (MDP) in both chemical colitis and severe sepsis. In the presence of GIV, macrophages enhance anti-bacterial pathways downstream of NOD2, clear microbes rapidly and concomitantly suppress inflammation. GIVs actions are mediated via its C-terminus, which directly binds the terminal leucine-rich repeat (LRR#10) of NOD2; binding is augmented by MDP and ATP, precedes receptor oligomerization, and is abolished by the 1007fs CD-risk variant which lacks LRR#10. Findings illuminate mechanisms that underlie protective NOD2 signaling and loss of function in the major 1007fs variant. In briefThis work reveals a mechanism by which macrophages use their innate immune sensor, NOD2, to protect the host against overzealous inflammation during bacterial infections, and the consequences of its loss, as occurs in the most important Crohns disease-risk variant. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/489574v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@139a1feorg.highwire.dtl.DTLVardef@ba5354org.highwire.dtl.DTLVardef@b4d933org.highwire.dtl.DTLVardef@11fe12e_HPS_FORMAT_FIGEXP M_FIG GRAPHIC ABSTRACT C_FIG HIGHLIGHTSO_LIGIV is a functional and direct interactor of the terminal LRR repeat of NOD2 C_LIO_LIMice lacking M[FE] GIV develop dysbiosis, protracted ileocolitis and sepsis C_LIO_LIMDP/NOD2-dependent protective host responses require GIV C_LIO_LICD-risk NOD2 1007fs variant lacking the terminal LRR#10 cannot bind GIV C_LI

immunology↗