Biology subjects

Hawthorne, K.

Publications and source records attributed to Hawthorne, K..

3 recordsLinked to original sources

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↗

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↗