Biology subjects

Sears, R. C.

Publications and source records attributed to Sears, R. C..

At least 19 recordsLinked to original sources

bioRxiv2026

MYC targeted de novo binders impair tumor growth

MYC is one of the most frequently dysregulated oncogenic drivers across many cancers, yet direct therapeutic targeting has remained difficult because its function is mediated by disordered regions and transient protein-protein interactions. Here we design proteins that bind epitopes within regions of MYC whose sequence is conserved between human and mouse, including intrinsically disordered motifs required for oncogenic activity. In vitro, the designs bind MYC with nanomolar affinity and in cells they engage MYC, disrupt interactions with MAX, and remodel MYC-associated protein complexes. Expression of the binders decreases cell proliferation across diverse MYC-dependent hematopoietic, liver, pancreatic, and patient-derived tumor models, and in an orthotopic pancreatic cancer model, binder-expressing tumor cells were selectively depleted. This work establishes de novo protein design as a generalizable strategy to therapeutically target intrinsically disordered transcription factors.

biochemistry↗

bioRxiv2026

Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells

Pancreatic ductal adenocarcinoma (PDAC) progression involves malignant cell state plasticity. Epigenetic changes underlie this plasticity, yet the PDAC cis-regulatory landscape remains understudied. To address this, we profiled 33 primary tumors and 7 metastases from 39 patients with single-cell ATAC-seq, paired with 10 single-cell RNA-seq profiles. We found that epigenetic GATA6+/KRT17+ co-accessibility identifies a classical-basal subtype-intermediate progenitor state (SIP) associated with better clinical outcomes. SIP cells display limited epigenetic reprogramming from premalignant epithelium and retain gastric-intestinal differentiation reminiscent of neoplastic precursors. Lineages without GATA6+/KRT17+ co-accessibility exhibit greater lineage and epithelial-mesenchymal plasticity. Classical PDACs that repress basal gene accessibility activate neural-like progenitor (NRP) and tuft lineage enhancers, whereas basal committed tumors display esophageal transdifferentiation. Compared to SIP, classical-NRP and basal committed tumors have poorer outcomes, and show distinct PD-1/PD-L1 immune proteomic phenotypes and prognostic myofibroblast epigenetic states, respectively. Our work reveals links between lineage reprogramming, EMT, and epigenetic progression in human PDAC.

cancer biology↗

bioRxiv2026

ACCREDIT: A Quality-Aware Agentic Engine for Cell-resolved Cross-modal Image Registration with Dynamic Iterative Tuning

Spatial omics across complementary modalities is transforming our understanding of tissue architecture. Realizing this potential requires accurate and robust registration of cross-platform molecular images with hematoxylin-and-eosin (H&E) sections, the primary morphological reference for pathology. Existing methods, however, often fail silently when image orientation is unknown, image contrast is inverted, or tissue overlap is incomplete, producing erroneous registrations without alerting users or attempting recovery. Here, we present ACCREDIT, a quality-aware agentic framework that redefines cross-modal registration as an adaptive decision-making process rather than a one-shot computation. ACCREDIT combines deterministic registration pipelines with a reference-free composite quality score that automatically evaluates registration quality and rejects plausible but biologically incorrect registrations. When registration quality is insufficient, a large language model (LLM)-based rescue agent autonomously diagnoses failure modes and selects targeted recovery strategies, while an optional strategy-learning module captures expert-validated corrections for future reuse. Across Xenium, CODEX, cell-boundary, and IHC-to-H&E registration tasks, ACCREDIT outperformed competing methods by detecting registration failures and improving alignment quality through automated recovery and rescue. Ultimately, ACCREDIT enables robust integration of histology and spatial molecular profiling, providing a foundation for translating spatial omics into routine H&E-based pathology workflows.

bioinformatics↗

bioRxiv2026

Spatially Resolved Epithelial States Delineate Immunosuppressive Niches of Impaired Myeloid Antigen Presentation in PDAC

Bulk transcriptomic classifiers stratify pancreatic ductal adenocarcinoma (PDAC) into classical and basal-like subtypes with prognostic and therapeutic relevance, yet increasing evidence indicates that these epithelial programs frequently coexist within individual tumors. How these intermediate states affect the local tumor microenvironment remains poorly defined. Here, we integrate multiplexed ion beam imaging (MIBI) with bulk RNA sequencing to resolve epithelial subtype identity at the level of spatially contiguous cancer nests and quantify their associated microenvironments. Across 47 primary tumor samples from 34 patients, we identified classical, intermediate, and basal cancer cell states at single-cell resolution and delineated discrete cancer nests with mixed or dominant subtype compositions. Distance-resolved spatial analysis reveals that basal-rich cancer nests are surrounded by locally immunosuppressive microenvironments characterized by reduced expression of MHC class II and co-stimulatory molecules in proximal myeloid cells, independent of myeloid abundance. These regions are enriched in fibroblast-dominated neighborhoods and distinct cell-cell interaction architectures. Using EcoTyper analysis of two independent bulk RNA-seq cohorts, including an OHSU discovery cohort (N = 277 patients) and TCGA as a validation cohort (N = 147 patients), we identified poor-prognosis tumor ecotypes enriched for basal epithelial states that similarly exhibited depleted myeloid antigen presentation signatures, linking spatial niche phenotypes to transcriptional ecotypes and patient outcomes. Together, these findings demonstrate that epithelial subtype programs in PDAC are organized at the level of spatially defined cancer nests and that basal cancer programs reside within localized niches of myeloid antigen presentation dysfunction, linking intratumoral architecture to immune suppression and clinical prognosis.

cancer biology↗

bioRxiv2026

Global mRNA 3'UTR lengthening in small-cell neuroendocrine carcinoma

Small-cell neuroendocrine carcinoma (SCNC) is a rare but highly malignant tumor subtype that primarily arises in the lung, also rarely in other organs, and as a consequence of treatment induced lineage transdifferentiation of prostate adenocarcinomas. The molecular convergence of SCNC across diverse tissues enables its identification through conserved SCNC-specific molecular markers, facilitating tumor subtype classification. As a critical post-transcriptional regulatory mechanism, alternative polyadenylation (APA) modulates 3'UTR length and significantly impacts tumor progression. However, its role in SCNC remains largely unclear. Here, we report a global 3'UTR lengthening pattern driven by APA in SCNC. We identified a set of conserved 3'UTR lengthening events across SCNCs of different tissue origins, which are strongly associated with neural development and related signaling pathways. Furthermore, we developed a neural network-based prediction model to classify SCNC by leveraging these specific APA signatures. Our study provides new insights into the post-transcriptional landscape of SCNCs and highlights APA signatures as promising biomarkers for SCNC identification.

cancer biology↗

bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗

bioRxiv2025

GNL3 SUMOylation is essential for DNA double-strand break repair by homologous recombination

DNA double-strand break (DSB) repair via homologous recombination (HR) is critical for maintaining genomic integrity and requires proper DNA end resection to generate single-stranded DNA (ssDNA) overhangs. However, the mechanisms governing this critical step in cells remains poorly understood. Here, we report that GNL3, a nucleolar GTP-binding protein, plays a key role in HR repair via regulating DNA end resection dependently on its SUMOylation. Ectopic expression of wild-type, but not the SUMO-defective K196R mutant, GNL3 completely abolished DNA damage response induced by knockdown of endogenous GNL3. GNL3 interacts with the BLM-DNA2 helicase-nuclease complex and is critical for DNA end resection and subsequent loading of RPA and RAD51. This interaction requires SUMOylation and SUMO-interacting motifs (SIMs) in both proteins. We further demonstrate that USP36, a nucleolar deubiquitinating enzyme, functions as a novel SUMO ligase for GNL3, while the SUMO protease SENP3 deSUMOylates GNL3. Notably, several breast cancer-derived GNL3 variants that disrupt its SUMOylation or SIM fail to interact with the BLM-DNA2 complex. Knockdown of GNL3 sensitizes HR-proficient breast cancer cells to etoposide or Olaparib treatment. Together, our results reveal that GNL3 SUMOylation is crucial for HR repair and suggest that targeting GNL3 SUMOylation may induce HR deficiency, thereby sensitizing breast cancers to DNA damage-inducing agents.

cell biology↗

bioRxiv2025

S3R: Spatially Smooth and Sparse Regression Reveals High-Dimensional Regulatory Networks in Spatial Transcriptomics

Spatial transcriptomics (ST) data demands models that recover how associations among molecular and cellular features change across tissue while contending with noise, collinearity, cell mixing, and thousands of predictors. We present Spatially Smooth Sparse Regression (S3R), a general statistical framework that estimates location-specific coefficients linking a response feature to high-dimensional spatial predictors. S3R unites structured sparsity with a minimum-spanning-tree-guided smoothness penalty, yielding coefficient fields that are coherent within neighborhoods yet permit sharp boundaries. In synthetic data, S3R accurately recovers spatially varying effects, selects relevant predictors, and preserves known boundaries. Applied to Visium-based ST data, S3R recapitulates layer-specific target-TF associations in human dorsolateral prefrontal cortex with concordant layer-wise correlations in matched single-cell data. In acute Haemophilus ducreyi skin infection, S3R converts spot-level gene expression mixtures into cell type-attributed expression fields, revealing per-cell type spatial gradients, and improving concordance of spatially variable gene calls when tests are applied to these demixed fields. In pancreatic ductal adenocarcinoma, S3R builds cross-cell-type, cross-gene co-variation tensors that quantify cell-cell interaction strength at gene-pair resolution and nominate interacting genes whose pathway enrichments align with established stromal-epithelial and immune crosstalk. An efficient implementation scales to large assays, and on a Xenium-based breast cancer dataset, S3R delineates the contributions at gene-gene, local neighborhood, and global context-level to target gene expression. Because responses and predictors in S3R are user-defined, it could flexibly address diverse biological questions within a single, scalable, and interpretable regression framework.

bioinformatics↗

bioRxiv2025

Myc and Kras cooperate in adult acinar cells to drive phenotypic heterogeneity, metastasis, and therapeutic resistance in a novel pancreatic cancer mouse model

Pancreatic ductal adenocarcinoma (PDAc) is a deadly malignancy, most commonly diagnosed in advanced stages when no curative treatments are available. The development of new models that aid ongoing investigation into the mechanisms by which it initiates, disseminates, and evades treatment is of the utmost importance. In vivo models that accurately recapitulate the features and spectrum of human pancreatic cancer are paramount to make a dent in this disease as two decades of the standard-of-care have failed to substantially improve survival. Here, we take advantage of our finding that post-translational stabiliziation of MYC downstream of the canonical PDAc driver, mutant KRAS, is an early event in PDAc progression to design a novel mouse model of PDAc progression based on deregulated, constituitive expression of Myc and mutant Kras in adult pancreatic acinar cells. Tumors from this KMC model histologically and molecularly recapitulate heterogeneity seen in human PDAc, with a high rate of metastasis to the liver. Cell lines derived from KMC autochthonous PDAc provide new models for orthotopic primary tumors that reliably metastasize to the liver and lung, providing important new tools to efficiently study the metastatic cascade and aid in the develoment of new therapeutics addressing metastatic disease. Cell lines represent distinct molecular subtypes with corresponding differential drug sensitivity. Toghether, this model provides a new and additional tool in the study of pancreatic cancer and the means by which it so deftly evades our best efforts at treatment.

cancer biology↗

bioRxiv2025

Long Noncoding RNAs Enforce Pancreatic Cancer Identity and Block Reprogramming

The Yamanaka factors (OCT4, SOX2, KLF4, and MYC; OSKM) can rejuvenate aging phenotypes in somatic cell types by resetting the epigenetic landscape. Curiously, most solid tumor cells remain largely resistant to reprogramming despite their well-documented plasticity, and the underlying mechanisms are unclear. Here, we combined genomic profiling and in vivo assays to investigate OSKM-mediated reprogramming of pancreatic ductal adenocarcinoma (PDAC). In the initial stages, we found that cancer-specific genes were refractory while mesodermal/ECM programs, normally silenced by PRC2, were aberrantly upregulated. A CRISPR interference screen for OSKM reprogramming coupled with functional analyses revealed that suppression of cancer-associated long noncoding RNAs (lncRNAs) erased malignant epithelial programs, restored tumor suppressor activity, and impaired tumorigenicity in vivo. We further identified that ATXN7L3-AS1 lncRNA sustains the PDAC malignant identity through its association with active epithelial oncogenic programs and poised PRC2-targeted developmental genes, thereby supporting both plasticity and memory. Thus, by exploring why cancer cells are resistant to reprogramming, we identify lncRNAs as gatekeepers of malignant identity, suggesting that targeting lncRNAs could be a generalizable therapeutic strategy in treating solid tumors.

cancer biology↗

bioRxiv2025

PIVOT: an open-source tool for multi-omic spatial data registration

Advances in spatial profiling have resulted in the generation of multi-omic atlases that span biological scales. In general, multiple workflows are required for image registration, coordinate registration, and spot deconvolution to integrate modalities. To improve the throughput of registration of multi-omic cohorts, we introduce PIVOT, a user-friendly and open-source interface for streamlined nonlinear registration. We demonstrate PIVOTs strengths through registration of three multi-omic datasets, and show comparison of its performance to existing workflows.

bioinformatics↗

bioRxiv2025

MicroCT enables simultaneous longitudinal tracking of murine pancreatic cancer progression and cachexia

Preclinical models of pancreatic ductal adenocarcinoma (PDAC) can greatly benefit from non-invasive imaging for evaluating disease progression and therapeutic response. Imaging approaches that can accurately and simultaneously track primary tumor growth, metastatic dissemination, and host cachexia over time are lacking. Here, we report an optimized dual-contrast micro-computed tomography (microCT) protocol for longitudinal imaging in orthotopic murine models of PDAC. This method enables high-resolution, volumetric quantification of orthotopic primary tumors, liver and lung metastases, and paraspinal skeletal muscle, providing a dynamic view of both tumor and host physiology. MicroCT primary tumor measurements strongly correlated with endpoint tumor weights and outperformed 2D ultrasound in early detection and volumetric accuracy, particularly for small or irregularly shaped tumors. This platform revealed heterogeneous metastatic kinetics across PDAC models and uncovered early, heterogeneous onset of skeletal muscle wasting, a hallmark of cancer cachexia. Notably, this protocol mimics clinical CT surveillance by enabling opportunistic cachexia assessment from tumor imaging datasets and offers substantial advantages over destructive endpoint analyses. Further, microCT radiation had no effect on our model endpoints. By capturing the temporal dynamics of tumor progression and host response, dual contrast microCT serves as a powerful translational platform for preclinical PDAC research and therapeutic testing. SignificanceDual-contrast microCT provides high-resolution, whole-body, non-invasive imaging in orthotopic murine PDAC models, enabling simultaneous tracking of tumor growth, metastasis, and skeletal muscle wasting-offering a clinically relevant, translational imaging platform.

cancer biology↗

bioRxiv2025

PIN1 Drives Cellular Plasticity and Immune Modulation in Chronic Pancreatitis

Background and AimsChronic pancreatitis (CP) is characterized by inflammation, fibrosis, and acinar-to-ductal metaplasia (ADM). PIN1, known to drive oncogenic signaling and cellular plasticity in cancer, has an unexplored role in CP. This study investigates PIN1s expression and function in CP pathogenesis using human tissues and mouse models. MethodsPIN1 expression was assessed in human CP tissue microarrays (TMAs) via immunohistochemistry (IHC) and cyclic immunofluorescence (CyCIF). Acute and chronic pancreatitis were induced in wild-type (WT) and PIN1 knockout (PIN1KO) mice using caerulein. Disease progression was monitored histologically, and immune profiling was conducted using flow cytometry. Pharmacological inhibition was performed using a small molecule PIN1 inhibitor-Sulfopin, and effects were evaluated by histology, qPCR, and cytokine analysis. Single-cell RNA sequencing (scRNA-seq) was performed on pancreatic tissues to perform pathway analysis and intercellular communication. ResultsPIN1 expression was elevated in human CP tissues, correlating with disease severity and ADM. In mice, both acute and chronic pancreatitis increased PIN1 expression, but only in our chronic PIN1KO mice displayed reduced pancreatic injury, fibrosis, ADM, and modulated immune infiltration. Pharmacological PIN1 inhibition mimicked the protective effects of genetic knockout, dampening inflammatory pathways. scRNA-seq revealed that PIN1 inhibition altered the intercellular communication networks between epithelial, immune, and stromal cells. ConclusionPIN1 drives cellular plasticity, immune modulation, and disease progression in CP. Targeting PIN1 may offer a therapeutic strategy to mitigate CP. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=184 HEIGHT=200 SRC="FIGDIR/small/653850v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@67f9fcorg.highwire.dtl.DTLVardef@4d4c1forg.highwire.dtl.DTLVardef@c099d7org.highwire.dtl.DTLVardef@b41aa5_HPS_FORMAT_FIGEXP M_FIG C_FIG Created in BioRender. Shah, V. (2025) https://BioRender.com/undefined

cell biology↗

bioRxiv2025

KDM5B expression is suppressed by MYC in a negative feedback loop to promote cell survival.

Both c-MYC and KDM5B are global regulators of gene transcription, cell identity, and master transcription factors in hematopoietic malignancies. In this study we link these two critical factors in a negative feedback loop that controls apoptosis and cell survival. We find the MYC specifically downregulates KDM5B, thereby inhibiting its transcriptional repressive functions. Loss of KDM5B abrogates the cell death response to MYC withdrawal in MYC-dependent cells, indicating KDM5B mediates cell death. We find that KDM5B regulates the MYC network, and specifically demethylates the MYC locus. In summary we have discovered a negative feedback loop between MYC and KDM5B. The MYC-dependent suppression of KDM5B leads to a global increase in H3K4me3 methylation, transcriptional activity, and increase cell survival and tumor progression.

cancer biology↗

bioRxiv2025

MYC Serine 62 phosphorylation promotes its binding to DNA double strand breaks to facilitate repair and cell survival under genotoxic stress.

Genomic instability is a hallmark of cancer, driving oncogenic mutations that enhance tumor aggressiveness and drug resistance. MYC, a master transcription factor that is deregulated in nearly all human tumors, paradoxically induces replication stress and associated DNA damage while also increasing expression of DNA repair factors and mediating resistance to DNA-damaging therapies. Emerging evidence supports a non-transcriptional role for MYC in preserving genomic integrity at sites of active transcription and protecting stalled replication forks under stress. Understanding how MYCs genotoxic and genoprotective functions diverge may reveal new therapeutic strategies for MYC-driven cancers. Here, we identify a non-canonical role of MYC in DNA damage response (DDR) through its direct association with DNA breaks. We show that phosphorylation at serine 62 (pS62-MYC) is crucial for the efficient recruitment of MYC to damage sites, its interaction with repair factors BRCA1 and RAD51, and effective DNA repair to support cell survival under stress. Mass spectrometry analysis with MYC-BioID2 during replication stress reveals a shift in MYCs interactome, maintaining DDR associations while losing transcriptional regulators. These findings establish pS62-MYC as a key regulator of genomic stability and a potential therapeutic target in cancers.

cancer biology↗

bioRxiv2025

Clonal Heterogeneity in Human Pancreatic Ductal Adenocarcinoma and Its Impact on Tumor Progression

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by profound desmoplasia and cellular heterogeneity, which cannot be fully resolved using traditional bulk sequencing approaches. To understand the contribution of this heterogeneity to PDAC biology, we analyzed a large cohort of primary human PDAC samples (n = 62), profiling 443,451 single cells and 53,236 spatial transcriptomic spots using a combined single-cell RNA sequencing and spatial transcriptomics approach. Our analysis revealed significant intratumoral heterogeneity, with multiple genetically distinct neoplastic clones co-existing within individual tumors. These clones exhibited diverse transcriptional states and subtype profiles, challenging the traditional binary classification of PDAC into basal and classical subtypes; instead, our findings support a transcriptional continuum influenced by clonal evolution and spatial organization. Additionally, these clones each interacted uniquely with surrounding cell types in the tumor microenvironment. Phylogenetic analysis uncovered a rare but consistent classical-to-basal clonal transition associated with MYC amplification and immune response depletion, which were validated experimentally, suggesting a mechanism driving the emergence of a more aggressive basal clonal phenotype. Spatial analyses further revealed dispersed clones enriched for epithelial-to-mesenchymal transition (EMT) activity and immune suppression, correlating with metastatic potential and colonization of lymph node niches. These dispersed clones tended to transition toward a basal phenotype, contributing to disease progression. Our findings highlight the critical role of clonal diversity, transcriptional plasticity, and TME interactions in shaping human PDAC biology. This work provides new insights into the molecular and spatial heterogeneity of PDAC and offers potential avenues for therapeutic intervention targeting clonal evolution and the mechanisms driving metastasis.

cancer biology↗

bioRxiv2025

Pancreatic cancer-intrinsic HuR regulates the pro-tumorigenic properties of extracellular vesicles

Pancreatic ductal adenocarcinoma (PDAC) tumors contain chaotic vasculature that limits immune surveillance and promotes early events in the metastatic cascade. However, current antiangiogenic therapies have failed in PDAC, and thus, it remains important to uncover mechanisms by which cancer cells signal to endothelial cells to increase angiogenesis. Our lab has shown that the tumor-intrinsic RNA-binding protein HuR (ELAVL1) plays an important role re-shaping the tumor microenvironment (TME) by regulating the stability and translation of cytokine encoding transcripts. Herein, we demonstrate that PDAC-intrinsic HuR influences endothelial cell function in the TME via extracellular vesicle (EV) signaling, an underexplored signaling axis in tumor progression. We found that HuR knockout (KO) tumors have impaired growth in an immunocompetent mouse model, and that administering purified wildtype (WT) EVs can increase tumor growth. Further, we observed that PDAC EVs contain HuR-dependent mRNA and protein cargoes relating to endothelial cell function and angiogenesis. Treatment of endothelial cells with HuR WT EVs strongly increased the expression of genes involved in barrier function and endothelial cell development, and directly increased their migratory and tube forming functions. In an immunocompetent orthotopic mouse model of PDAC, we showed that HuR increases endothelial cell presence and sprouting, while decreasing ICAM-1 expression. Importantly, we found utilizing a genetic EV reporter, that decreased ICAM-1 within WT tumors occurs in endothelial cells that have imported PDAC EVs, suggesting that this signaling axis is directly modulating endothelial cell behavior in vivo. Collectively, our data reveal a new role of HuR in EV signaling to endothelial cells, promoting angiogenesis while restricting endothelial cell leukocyte trafficking behavior.

cancer biology↗

bioRxiv2025

mRNA stability factor HuR promotes immune evasion in pancreatic ductal adenocarcinoma

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by a limited infiltration of tumor-specific T cells and anti-tumor T cell activity. Extracellular factors in the PDAC TME have been widely reported to mediate immune suppression, but the contribution from tumor-intrinsic factors is not well understood. The RNA-binding protein, HuR (ELAVL1), is enriched in PDAC and negatively correlates with T cell infiltration. In an immunocompetent Kras-p53-Cre (KPC) orthotopic model of PDAC, we found that genetic disruption of HuR impaired tumor growth due to a novel role of HuR inducing T-cell suppression. Importantly, we found that HuR depletion in tumors enhanced both T cell number and activation states and diminished myeloid phenotypes by comprehensive spatial profiling of the PDAC TME. Mechanistically, HuR mediated the stabilization of mTOR pathway transcripts, and inhibition of mTOR activity rescued the impaired function of local T cells. Translating these findings, we demonstrated that HuR depletion sensitized PDAC tumors to immune checkpoint blockade, while isogenic, wildtype tumors are resistant. For the first time, we show that HuR facilitates tumor immune suppression in PDAC by inhibiting T cell infiltration and function and implicate targeting HuR as a potential therapeutic strategy in combination with immunotherapy. SIGNIFICANCEThis study identified a novel mechanism that HuR supports pancreatic tumor growth by restricting T cell infiltration, promoting immune evasion. Our work supports targeting strategies against HuR in PDAC with the goal of enhancing PDAC sensitivity to immune-based cancer therapies, such as checkpoint blockade and T cell transfer.

cancer biology↗