Biology subjects

Choi, S.

Publications and source records attributed to Choi, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Brassinosteroid-regulated transcription factors confer epigenetic changes that repress plant immunity

When organisms encounter pathogens, they rapidly activate complex defense programs to ensure survival. While these immune responses are vital, they often also incur trade-offs, such as reduced growth and development and must therefore be tightly controlled 1,2. In this study, we reveal that the steroid hormones brassinosteroids (BRs) contribute to this control in Arabidopsis thaliana by repressing immunity-related genes. We provide evidence that the BR-regulated basic helix-loop-helix (bHLH) transcription factor CESTA (CES), along with its homologs BR ENHANCED EXPRESSION (BEE)1-3, mediate DNA methylation changes at transposable element (TE)-rich loci containing nucleotide-binding leucine-rich-repeat (NLR)-type receptor genes, including SUPPRESSOR OF NPR1-1 CONSTITUTIVE 1 (SNC1). These CES-induced methylation changes correlate with altered splicing of SNC1 pre-mRNA, a process that requires the BR receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1). In support, we show that CES associates with components of the chromatin remodeling and splicing machinery. Together, our findings reveal a previously unrecognized BR-induced mechanism that modulates the epigenetic and post transcriptional regulation of immune genes, enabling plants to prioritize growth over defense. Significance statementSteroid hormones are powerful regulators of growth but also act as potent suppressors of immunity, with well-established clinical applications, for example in treating autoimmune diseases in humans. In plants, the steroid hormones brassinosteroids (BRs) exert similar effects. Here, we uncover that BR-mediated immune suppression involves DNA methylation changes and alternative splicing of a subset of immune receptor genes, that govern resistance responses mediated by the plant hormone salicylic acid. We provide evidence for a function of specific bHLH transcription factors in this process that link BR signaling to chromatin remodelling and RNA processing. Thereby our study reveals a novel mode of steroid hormone activity in immune repression, which involves epigenetic and posttranscriptional adjustment of immune receptor function.

plant biology↗

bioRxiv2026

PA-SfM: Tracker-free differentiable acoustic radiation for freehand 3D photoacoustic imaging

Three-dimensional photoacoustic imaging (3D PAI) has shown great potential in preclinical studies and clinical implementations, while it commonly has sparse sensor arrays, limiting both spatial sampling and the field of view (FOV). Freehand scanning could overcome these limitations through anatomy-adaptive scanning that extends spatial coverage and provides complementary views beyond the fixed array aperture, but its flexibility is conventionally constrained by the need for motor feedback or external pose tracking. Here we introduce PA-SfM, a tracker-free structure-from-motion (SfM) framework that recovers multiple poses directly from PA measurements with superior precision, enabling freehand 3D PAI without external pose measurements. PA-SfM integrates a differentiable acoustic radiation model with hierarchical optimization and rigid array constraints, it jointly estimates inter-view transformations and reconstructs 3D volumes. The performance of PA-SfM was demonstrated in numerical simulations, animal studies and human imaging experiments. Compared with motor encoder-based fusion of the mechanically scanned system, PA-SfM produced sharper and more continuous vascular reconstructions with an expanded FOV. In controlled quantitative validations, PA-SfM achieved high reconstruction fidelity, with PSNR values over 40 dB and SSIM values above 0.98 relative to ground truth or known pose reference reconstructions. These results demonstrate that PA-SfM enables robust freehand 3D PAI, with particular potential for clinical implementation of large-scale freehand imaging. The source code is publicly available at https://github.com/JaegerCQ/PA-SfM.

bioengineering↗

bioRxiv2026

AI predictions and the expansion of scientific frontiers: Evidence from structural biology

Artificial intelligence holds the potential to expand the frontier of scientific research, yet recent work has raised concern that it may instead narrow scientific attention to well-established areas. Here, leveraging the 2021 release of AlphaFold2 as a quasi-experimental opportunity, we provide field-level evidence that AI can redirect collective attention toward more novel research targets. Tracking 245,396 experimental structures in the Protein Data Bank, we show that a long-running decline in the study of novel proteins halted after AlphaFold2s release, with the shift concentrated among studies citing AlphaFold2 and targets with high-confidence predictions. This pattern extends to 248,191 downstream papers that consume structural knowledge, where engagement with genes lacking experimental structures and with understudied human genes increased since 2021. Amid rising concern that AI may reinforce scientific canons, our findings offer an early field-level case where AI predictions expand scientific frontiers, consistent with the idea that the real-world consequences of AI on science depend on where their informational gains are greatest. These results suggest AI can complement human knowledge and redirect collective attention in science, with broad implications for emerging AI for science models.

bioinformatics↗

bioRxiv2026

METTL14-dependent m6A modification restrains interferon signaling to prevent myocarditis and dilated Cardiomyopathy

The impact of inflammation on heart failure is increasingly recognized; but how cardiomyocyte restrains innate immune activation remains poorly defined, and nor does the role of N-methyladenosine (mA) modification in maintaining cardiac immune homeostasis. Here, we demonstrate that cardiomyocyte-specific deletion of the mA methyltransferase METTL14 triggers myocarditis, dilated cardiomyopathy, and premature lethality. Meanwhile, widespread hypomethylation and upregulation of innate immune and necroptosis-related transcripts in Mettl14-deficient hearts exemplified by IFN-1 and STAT1. Mechanistically, METTL14 deficiency promotes RIPK1 accumulation thereby priming cardiomyocytes for necroptosis and inflammatory cell death. Genetic ablation of IFN-I receptor Ifnar1 can largely rescue the processes and improve cardiac function and survival. Furthermore, METTL14 loss disrupts mitochondrial integrity and autophagy/mitophagy flux, suggesting mitochondrial dysfunction-driven innate immune activation upstream of IFN-I signaling. Collectively, these findings identify METTL14-mediated mA modification as a critical safeguard against cardiomyocyte-intrinsic IFN-I signaling and necroptosis and establish an epitranscriptomic-innate immune axis that drives inflammatory heart failure.

pathology↗

bioRxiv2026

Membrane progesterone receptor signaling reverses hyperglycemia and insulin resistance in obese mice

Progesterone (P4) plays key roles in reproductive and metabolic function and signals through two receptor classes: classical nuclear receptors that regulate gene transcription and membrane progesterone receptors (mPR) that mediate rapid, non-genomic signaling. Whether mPR signaling influences systemic glucose homeostasis remains unclear. Here, we investigated whether mPR activation regulates glucose homeostasis and insulin sensitivity. Using the selective mPR agonist OD02-0, we show that mPR activation enhances glucose uptake in skeletal muscle and hepatocytes, associated with AMP-activated protein kinase (AMPK) activation. In HepG2 cells, mPR activation induces metabolic reprogramming characterized by reduced mitochondrial respiration and increased glycolytic flux. Pharmacological inhibition of AMPK suppresses this effect, indicating that these responses require AMPK activity. In diet-induced obese mice, chronic mPR activation reduces fasting glucose and insulin levels, improves glucose tolerance, and restores glucose-stimulated insulin secretion without detectable toxicity. Integrated proteomic and phosphoproteomic analyses in mouse liver reveal modulation of AMPK signaling and inhibition of mTORC1. Transcriptomic changes were limited, supporting a predominantly non-genomic mode of action. Together, these findings identify mPR signaling as a regulator of glucose homeostasis that engages central energy-sensing pathways to improve metabolic control in obesity.

physiology↗

bioRxiv2026

Cellular Senescence Drives Zinc Accumulation and Transporter Dysregulation in Intestinal Epithelial Cells

Zinc is essential for life, and its regulation is tightly controlled by numerous transporters. As we age, our micronutrient levels, intake, and absorption change. Additionally, senescent cells increase with age and can contribute to the progression of age-related diseases. The study of Zn homeostasis in senescent intestinal cells is a relatively unexplored area that we aimed to investigate. Using two models to induce senescence in intestinal epithelial cells--etoposide treatment and {gamma}-irradiation--we observed that Zn levels increased in the cells, likely due to the upregulation of Zn transporters ZIP4 and ZnT7. This upregulated Zn seems to accumulate in the Golgi apparatus, and when Zn accumulation is blocked through chelation, a rescue effect occurs, marked by a decrease in senescence markers. This research emphasizes the role of Zn in senescent cells and its possible involvement in the development of senescence and the disrupted Zn homeostasis seen with aging.

cell biology↗

bioRxiv2026

Quantifying Behavioral Structure and Persistence in Open-Field Assays Using Entropy and Spectral Metrics

Traditional open-field assays quantify rodent behavior using low-dimensional scalar metrics that often overlook dynamical and temporally dependent aspects of spontaneous behavior. Here, we establish a high-throughput framework that integrates multi-camera 3D pose estimation from AVATAR-3D (1) with unsupervised autoregressive hidden Markov modeling using Keypoint-MoSeq (2-4) to transform recordings into time sequences of discrete, recurring behavioral units termed syllables. Drawing inspiration from information theory (5) and spectral analysis of Markov systems (6,7), we compute Shannon entropy and the second-largest eigenvalue (Eigen2) of the syllable transition matrix. Entropy and Eigen2 offer complementary lenses through which spontaneous behavior can be understood--one capturing dispersion of behavioral expression, the other reflecting temporal persistence and mixing dynamics. Together, these metrics quantify the organization of behavior as a stochastic dynamical system rather than a collection of isolated actions.

animal behavior and cognition↗

bioRxiv2026

Evolution of oncogene amplification across 86,000 cancer cell genomes

High-level copy-number (CN) amplification (HLAMP) is a major mechanism of oncogene activation in human cancer. Despite progress in therapeutically targeting amplified oncogenes, the processes underlying amplicon evolution remain incompletely understood, leaving critical knowledge gaps in their etiology and mechanisms of therapeutic response. To address this, we analyzed the evolutionary trajectories of HLAMPs using single-cell whole-genome sequencing data from 86,239 cancer cells across 93 patients and 9 experimental systems. We found that cell-to-cell CN variability provides a quantifiable readout of HLAMP mechanism, clearly distinguishing extrachromosomal circular DNA (ecDNA) from intrachromosomal amplification (ICamp) through characteristic CN distributions that reflect distinct modes of segregation and correspond to clonal architecture. Notably, ICamp events frequently showed multiple amplitude peaks specific to subclones, indicating punctuated shifts in oncogene dosage through numeric or structural modulatory mechanisms with transcriptional impact. In contrast, ecDNAs exhibited broad, continuous CN distribution with extreme high-copy outliers, consistent with asymmetric segregation. The CN and structural diversity of ecDNA regions enabled systematic deconvolution of ecDNA subspecies and estimation of their per-cell abundance, revealing the history of ecDNA-mediated oncogenesis at single-nucleotide resolution. We observed ecDNA diversification through internal rearrangements across cases and, notably, convergent evolution in glioblastoma cases marked by multiple, recurrent acquisition of EGFR-targeting ecDNAs. Finally, single-cell genome-based identification of ecDNAs showed substantial discrepancy with bulk genome graph-based predictions and reliably distinguished actively maintained ecDNAs from historical genomic footprints after chromosomal re-integration. These findings reveal marked tissue-type specificity of ecDNAs, suggesting that ecDNA-mediated oncogenesis may depend on a permissive tissue context.

genomics↗

bioRxiv2026

Disrupted Sleep-Dependent Neural Oscillations and Transcriptomic Changes in the Cacna1g Loss-of-Function Mouse Model Implicated in Schizophrenia

Sleep is an essential biological process for maintaining brain function, and impaired sleep microarchitecture is a well-established feature of schizophrenia (SCZ). Rare loss-of-function variants in CACNA1G, encoding the T-type calcium channel CaV3.1, confer substantial risk for SCZ, implicating sleep-regulatory circuits in disease pathophysiology. Here, we first show that among individuals with SCZ, carriers of rare CACNA1G missense variants exhibit more pronounced alterations in sleep neurophysiology than non-carriers, identifying a human phenotype suggestive of altered channel function. Motivated by this observation, we examined the consequences of Cacna1g loss of function in mice. Cacna1g deficiency produced profound disruptions in sleep microarchitecture, including reduced sleep spindles, altered slow oscillations, impaired spindle-slow oscillation coupling, and reduced cortical synchrony--closely recapitulating neurophysiological signatures observed in individuals with schizophrenia. Beyond sleep structure, Cacna1g loss disrupted the normal coordination of brain rhythms across the 24-hour cycle, most notably abolishing diurnal modulation of theta oscillations. At the molecular level, Cacna1g loss uncoupled sleep-wake state from gene and protein regulation, producing widespread, sleep-phase-biased transcriptional and synaptic alterations across brain regions and cell types, particularly in cortical excitatory neurons. These network and molecular disruptions were accompanied by behavioral hyperactivity during the active phase. Together, these findings establish CACNA1G/CaV3.1 as a key regulator linking sleep-dependent brain dynamics to molecular homeostasis and behavior, and provide a mechanistic framework through which genetic risk for SCZ may drive disease-relevant sleep and circuit dysfunction. One Sentence SummaryLoss of CACNA1G disrupts sleep rhythms and gene regulation, creating a mismatch between brain state and behavior linked to schizophrenia.

neuroscience↗

bioRxiv2025

Longitudinal Resting-State fMRI of Awake Mice During Habituation: Stress, Head Motion, and Functional Connectivity

Awake mouse fMRI is a powerful tool for both neuroscience and translational research. To minimize head motion during scanning, habituation under physical restraint is commonly used. However, it remains unclear how stress levels and head motion evolve during habituation, particularly within the MRI environment. To address this, we repeatedly measured plasma corticosterone (CORT) levels in three groups of mice - controls, mice habituated outside the MRI magnet, and mice habituated within the fMRI environment - and acquired longitudinal resting-state fMRI data daily during an eight-day habituation period and again 15 days post-habituation at 15.2 T. We found that CORT levels initially increased by approximately twofold and gradually decreased during habituation outside the magnet, whereas in mice habituated within the fMRI environment, CORT levels increased two- to fourfold and remained elevated throughout the habituation period. One week after habituation, CORT levels returned to baseline in both groups. Throughout all resting-state fMRI scanning sessions, head motion and functional connectivity remained stable, likely due to the well-designed restraint cradle that permitted paw movement. These results suggest that additional habituation days do not further reduce stress, provided that head motion remains within acceptable limits.

neuroscience↗

bioRxiv2025

Structural basis of cyclic phytocytokine recognition by the HSL3/NUT receptor

Plant receptor kinases perceive diverse peptide signals to coordinate stress responses and developmental programs. The HAESA-LIKE 3 (HSL3/NUT) receptor recognizes CTNIP/SCREW phytocytokines--disulfide-stabilized cyclic peptides that regulate immune signaling and stress adaptation. However, how HSL3 distinguishes these structurally constrained cyclic peptides from linear signaling molecules remains unknown. Here we report near-atomic resolution cryo-EM structures of HSL3 in apo and CTNIP448-70-bound states at [~]2.6 [A], using Arabidopsis CTNIP4 as a representative family member, revealing distinct mechanisms for cyclic peptide recognition. The conserved CTNIP motif occupies a negatively charged pocket in HSL3s C-terminal region through a combination of polar contacts, hydrogen bonds, salt bridges, and van der Waals interactions. The receptor employs a two-step recognition mechanism--electrostatic steering followed by motif anchoring--that enables rapid ligand capture and release, consistent with the transient nature of stress signaling. Notably, an N-glycan at Asn449 directly contacts the CTNIP4 peptide, establishing glycosylation as an active participant in ligand recognition. Structure-guided mutagenesis combined with reactive oxygen species (ROS) burst assays confirmed the functional importance of key binding interfaces. N-terminal truncation experiments revealed a minimal active fragment: CTNIP451-70 supported both rapid ROS production and sustained seedling growth inhibition, whereas the shorter CTNIP454-70 variant retained ROS activity but failed to trigger long-term seedling growth inhibition. Structure-guided coevolutionary analysis across plant lineages reveals patterns of both conserved and variable receptor-ligand interfaces, highlighting evolutionary flexibility while preserving core features of recognition. These conserved recognition principles, mediated by receptor glycosylation and evolutionary plasticity, enable specificity in peptide signaling with implications for engineering stress-resilient crops.

plant biology↗

bioRxiv2025

Patterns of Ocular Dominance are in the Eye of the Beholder

Ocular Dominance Columns (ODCs), structures in the early visual cortex that demarcate inputs from each eye, have been observed in a wide range of mammals. The extent and arrangement of these columnar structures can vary drastically from species to species, and even along the visual cortex of a single individual. While previous studies show that these structures can form by competitive Hebbian learning, the relationship between system parameters and the resulting organizational patterns remains unclear. Here, we use a mesoscopic model of V1 development to explain how the different observed patterns of ocular dominance (columns, islands, and monocular) can arise through local Hebbian competition, as a function of the density of projections from each eye and cortical interaction strengths. We argue that our results explain the broad cortical organizational differences between species which have forward-facing versus steeply angled eyes. We additionally show that spatially varying retinal input projections, which can arise from a combination of retinotopy and varying cell density, can lead to coexistence of multiple ocular dominance patterns along the cortical sheet, consistent with experimental observations.

biophysics↗

bioRxiv2025

Peri-Head Distance Coding in the Mouse Brainstem

Perceiving object distance in peri-personal space is essential for guiding movement and avoiding danger. During active sensation, distance information is often anchored to the body via touch; yet how early somatosensory circuits extract distance information from tactile inputs remains unclear. Here, we investigate how second-order neurons in the mouse whisker brainstem encode peri-head distance. Using in vivo extracellular recordings in awake mice in a naturalistic wall-passing paradigm, we find brainstem neurons employ two distance-coding schemes: a "proximity" code, where firing increases monotonically as objects approach the face; and a "map" code, where neurons exhibit peak tuning at specific distances to collectively tile peri-head space. The map code outperforms proximity code in population decoding of distance. Perturbation experiments reveal multi-whisker integration and internuclear inhibition contribute to the generation of map-like tuning. These findings highlight a previously underappreciated computational role for brainstem circuits, where inhibition acts as a neural comparator to transform proximity-based sensory inputs into a map-like representation of peri-personal space.

neuroscience↗

bioRxiv2025

Computational mechanisms for temporal integration in the anterior claustrum

AbstractThe claustrum, with its extensive reciprocal connections to nearly all cortical regions, has long been hypothesized as a key hub for integrating diverse cognitive, sensory and motor information. However, despite its anatomical connectivity, whether and how it functionally integrates different inputs to generate coherent representations has remained unclear. Here, we developed a recurrent neural network (RNN) trained via supervised learning on behavioral metrics of delayed escape--a behavioral paradigm that requires integration of temporally separated task-relevant signals. A subset of RNN neurons exhibited dynamics similar to those of anterior claustral neurons during this behavior. These neurons formed a recurrent cluster, a structure supported by in vitro stimulation experiments in claustral brain slices. We analyzed the computational properties of this claustrum-like cluster via dimensionality reduction of population activity. The network showed nonlinear integration of temporally distributed inputs and increased synergistic information. Rather than settling into attractors, integrated information was dynamically encoded along continuously evolving neural trajectories. Notably, similar trajectory patterns associated with dynamic integration were observed in claustral recordings, suggesting the models biological plausibility. We propose that the anterior claustrum dynamically integrates task-relevant input signals over time and broadcasts the evolving representation to downstream brain regions capable of reading and interpreting it in a context-dependent manner.

neuroscience↗

bioRxiv2025

T cell costimulatory and inhibitory signals differentially modulate LAT condensate nucleation propensity after TCR ligation

Linker for activation of T cells (LAT) is a membrane-surface scaffold protein that assembles key signaling molecules upon T cell receptor (TCR) activation. Recent observations have revealed LAT assembly occurs in discretized condensates traceable to single molecular TCR activation events. Moreover, the condensation process occurs abruptly, but after a distinct delay, indicative of a type of phase transition. Here we examine the effects of costimulatory (CD80, CD86) and inhibitory (PD-L1) ligands on the nucleation propensity of LAT condensation. We utilize single molecule mobility tracking to resolve the moment a pMHC molecule binds to TCR combined with intracellular imaging to measure the time delay between pMHC:TCR binding and nucleation of the corresponding LAT condensate. These delay time distributions reflect the propensity function for stochastic nucleation of the LAT condensate and provide a measure of the effective signal strength from a single, activated TCR. The results reveal that CD28 stimulation by CD80 or CD86 causes a distinct reduction in the mean delay time to LAT condensation while PD-L1 is mildly antagonistic to the process. Collectively, these observations strengthen evidence that probability and timing of the LAT nucleation process itself is tightly associated with signal propagation downstream from individual TCR activation events.

biophysics↗

bioRxiv2025

Inhibitory control and error processing in Obsessive-Compulsive Disorder: A mega-analysis of task-based fMRI data by the ENIGMA-OCD consortium

ObjectiveObsessive-compulsive disorder (OCD) is a chronic condition in which impaired inhibitory control and excessive error monitoring may contribute to the maintenance of obsessions and compulsions. This mega-analysis investigates neural activation during response inhibition and error processing using adult and pediatric data from the ENIGMA-OCD consortium and the ABCD study. MethodsIndividual participant data was uniformly processed using HALFpipe to extract statistical maps for response inhibition and error processing contrasts. Bayesian multilevel models were used to assess regional and whole-brain effects of OCD, with additional analyses examining the association between the OCD clinical profile and task-related activation. ResultsAcross inhibitory control tasks, both individuals with OCD and control participants showed robust activation in regions implicated in response inhibition and error processing. During response inhibition, compared to controls, adults with OCD showed stronger somatomotor cortex activation, while children with OCD showed stronger occipital cortex activation. Children with likely OCD from the ABCD cohort showed reduced activity in the frontoparietal network in the anterior insula/frontal operculum region. During error processing, relative to controls, adults with OCD showed weaker activation in fronto-striatal regions, while children with OCD showed stronger activation in frontoparietal and attention networks. Greater OCD symptom severity was associated with weaker task-related activation in adults and stronger activation in children during response inhibition. ConclusionCase-control differences in brain activation during inhibitory control varied by age group and task contrast. Symptom severity emerged as the main clinical correlate of activation during inhibition, suggesting that inhibitory control deficits in OCD may be both state-dependent and developmentally specific.

neuroscience↗

bioRxiv2025

Essential Resources for Curated Immune Markers and Antibody Panels in Cytometry Analysis

The immune system, fundamental to numerous biological research fields, is increasingly investigated at single-cell resolution using high-dimensional flow cytometry and mass cytometry technologies. These approaches require comprehensive immunomarker information and carefully designed antibody panels that address the technical challenges of isotopic and spectral overlap inherent in metal/fluorescent-labeled antibodies. While immune cell markers have been extensively characterized and systematically catalogued, antibody panel information remains fragmented across the literature. To bridge this critical gap, we present ImapDB (Immune cell Marker and Panel Database), a novel Python-based graphical user interface that consolidates curated information on cell markers and antibody panels. ImapDB integrates data from commercial guidebooks, peer-reviewed literature, and validated research sources, currently focusing on normal human immune cell states. The database encompasses 127 distinct immune cell subtypes with over 350 validated markers and includes 45 commercial and 23 custom research antibody panels. Available on GitHub (https://github.com/kimlab-cnu/Cell_Marker_GUI), ImapDB serves as a centralized repository designed to streamline immune profiling assays and enhance research efficiency.

bioinformatics↗

bioRxiv2025

VEGFR2 blockade overcomes acquired KRAS G12D inhibitor resistance driven by PI3Kγ activation

KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent studies have characterized features associated with primary and acquired resistance to KRAS inhibitors, strategies to overcome such resistance, particularly in the context of gastrointestinal cancers, remain underexplored. Here, we have generated nine human gastrointestinal cancer models, including three patient-derived organoids (PDOs), with acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. Using single-cell RNA sequencing analysis, we identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) signatures in the resistant model compared to the parental PDO. Across all resistant models, VEGFA expression and VEGFR2 phosphorylation were uniformly elevated, which were driven by AKT activation and SP1 nuclear translocation. Mechanistic investigations uncovered increased PI3K{gamma} activity in MRTX1133-resistant models via complex formation of KRAS with p110{gamma} and p101. This leads to an autocrine VEGFA-VEGFR2 signaling loop formation and EMT induction. Therapeutically, the disruption of VEGFA-VEGFR2 signaling restored MRTX1133 sensitivity and inhibited EMT. Furthermore, cancer-endothelial paracrine signaling amplified angiogenesis, hypoxia, and EMT signatures in cancer cells and simultaneously promoted endothelial cell proliferation, reinforcing an adaptive feedback mechanism. In a mouse model of MRTX1133-resistant tumor xenograft, a combination of anti-VEGFR2 therapy and MRTX1133 more effectively reduced tumor growth, angiogenesis, and proliferation markers than monotherapy without significant body weight change. These findings establish VEGFA-VEGFR2 signaling by PI3K{gamma} activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers. HighlightO_LIVEGFA-VEGFR2 signaling activation is a common feature of MRTX1133 resistance in KRASG12D cancer cells C_LIO_LINuclear translocation of SP1 by AKT activation promotes VEGFA transcription in MRTX1133-resistant models C_LIO_LIInteraction of p110{gamma}-p101 with KRAS activates PI3K{gamma} in the resistant models C_LIO_LIVEGFA-VEGFR2 inhibition reverses MRTX1133 resistance in vitro and in vivo C_LI

cancer biology↗