Biology subjects

Morton, J. P.

Publications and source records attributed to Morton, J. P..

17 recordsLinked to original sources

bioRxiv2026

TiSAM: fusing spatial and histopathology foundation models for whole-slide image segmentation

Semantic segmentation of whole-slide images (WSIs) quantifies tissue composition and architecture, but existing models require extensive annotation and lose accuracy as the number of tissue classes increases or on heterogeneous, cross-scanner datasets. Here, we present the Tissue Segment Anything Model (TiSAM), which fuses SAM3 spatial features with UNI2-h pathology features within a multi-scale decoder. Because public benchmarks contain few tissue classes, we release MegaMouse, comprising 36,833 annotations of 52 tissue classes from 12 mouse organs, and an 11-class human pancreas dataset. TiSAM achieved the highest overall performance across four public datasets compared to existing convolutional neural network and vision transformer models, maintained high accuracy on MegaMouse, and maintained high accuracy in the human pancreas dataset when trained on as few as 5 annotated WSIs where previous integrations of SAM with pathology foundation models did not. TiSAM segmentations were also more consistent across eight slide scanners compared to other models. These results establish TiSAM as a general and highly adaptable framework for tissue segmentation, enabling studies containing many tissue classes, limited annotations, or images from multiple scanners.

bioinformatics↗

bioRxiv2026

Engineering tunable synthetic fibrotic niches to model acinar-to-ductal metaplasia in 2D pancreatic culture systems

Acinar-to-ductal metaplasia (ADM) is an early pancreatic cell-state transition associated with injury, inflammation, and progression toward pancreatic intraepithelial neoplasia (PanIN). Although genetic and inflammatory drivers of ADM are well established, the contribution of extracellular-matrix mechanics is difficult to isolate because tissue stiffening is accompanied by changes in matrix composition and soluble signaling. Here, we describe a two-dimensional polyacrylamide (PAA) hydrogel platform that independently varies substrate stiffness and adhesive ligand presentation for murine pancreatic acinar 266-6 cells. Hydrogels approximate soft pancreatic tissue (0.50 kPa), a transitional mechanical condition (4.48 kPa), and fibrotic tissue (18.29 kPa). RGD provides a conventional adhesive cue relevant across healthy-to-fibrotic extracellular-matrix states, whereas incorporation of laminin-derived isoleucine-lysine-valine-alanine-valine (IKVAV) creates a more basement-membrane-like environment consistent with preservation of acinar identity. The platform was also adapted to include gelatin, a collagen-derived protein used here to model a more collagen-rich fibrotic matrix context. Peptide coupling is calibrated using fluorescently labeled RGD, and responses after 3 days are assessed by morphology, alpha-amylase 2 (AMY2), Yes-associated protein (YAP) nuclear-to-cytoplasmic localization, and sex-determining region Y-box transcription factor 9 (SOX9). Increasing stiffness increased nuclear YAP localization and reduced AMY2 expression. IKVAV-containing conditions supported greater attachment on softer matrices and partially preserved acinar-like phenotype on stiff gels despite elevated nuclear YAP. Across all ligand conditions, increasing stiffness reduced roundness and geometric regularity/solidity and increased aspect ratio; on gelatin-modified hydrogels, these phenotypic changes corresponded to increased cell-area-normalized SOX9 fluorescence. Together, these readouts identify a stiffness-dependent shift from an acinar-associated state toward an ADM-associated ductal phenotype, while ligand context modulates how this mechanical response is expressed. This protocol provides a controllable, adaptable system for separating mechanical and biochemical extracellular-matrix inputs during pancreatic phenotypic plasticity.

cancer biology↗

bioRxiv2026

Viscoelasticity drives EMT in pancreatic intraepithelial neoplasia

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic adenocarcinoma (PDAC) and therefore critical to understand for identifying early-stage diagnostic and therapeutic targets. During PanIN, epithelial-to-mesenchymal transition (EMT) of pancreatic epithelial cancer cells is a crucial event which promotes invasion and early dissemination of cells into circulation before the full development of PDAC tumours. Changes in tissue mechanics are apparent during progression from PanIN to PDAC and increased local and global elasticity has been mathematically modelled in PanIN tissue as a predictive tool for diagnostics and development of personalized therapies. Aside from elasticity, viscoelasticity is emerging as a key feature of cancer which affects tissue mechanics through a combination of elastic and viscous components. Viscoelasticity has recently been shown to drive mechanosensitive cell behaviour and is known to change dramatically in PDAC progression. Hydrogels, as water-swollen polymer networks, are effective extracellular matrix (ECM) models that can recapitulate the viscoelastic properties of natural tissue. Despite this, hydrogels developed for studying cell behaviour in PanIN use purely elastic materials or have neglected the viscous component. Here, using PDAC mouse models, we show that viscoelasticity dynamically alters between healthy and PanIN-bearing tissue and have decoupled the role of elasticity and viscosity during EMT of pancreatic epithelial cancer cells using two-dimensional (2D) polyacrylamide (PAAm) hydrogels. Our work shows viscosity is critical in driving phenotypic changes associated with EMT in a pancreatic epithelial cancer cell line. These findings identify viscosity as an integral component of cell mechanosensing as PanIN develops, which may contribute to initial metastatic events via dissemination from the developing primary tumour. This should be explored further to potentially reveal novel diagnostic and therapeutic targets.

cancer biology↗

bioRxiv2025

Radiotherapy drives lung metastasis in PDAC via a RhoGTPasesignaling shift towards MRCK-dependency

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with an extremely poor prognosis, partly owing to its highly metastatic nature. Although radiotherapy is an effective and potentially curative treatment modality, research over the last few decades has indicated that it may induce a more metastatic phenotype in surviving cancer cells. We demonstrate for the first time that clinically relevant doses of image-guided targeted radiotherapy induce metastasis in a genetically engineered KPC mouse model of PDAC. Furthermore, this induction is largely driven by an organotropic switch towards lung metastasis. Using an in vitro RNAi screening approach, we identified a key role for myotonic dystrophy-related Cdc42-binding kinase (MRCK) in driving this response. MRCK activity was spatially upregulated at the plasma membrane in response to radiotherapy in PDAC cell lines as well as at the invasive margins of PDAC tumors. This upregulation of activity was maintained in metastases, suggesting an important role for MRCK in not only triggering local invasion in response to radiotherapy but also promoting distant metastases. Importantly, inhibition of MRCK with a small-molecule inhibitor (BDP9066) specifically opposed radiation-driven MRCK upregulation and pro-metastatic response.

cancer biology↗

bioRxiv2025

ROCK2 inhibition has a dual role in reducing ECM remodelling and cell growth, while impairing migration and invasion

The Rho-associated coiled-coil containing protein kinases 1/2 (ROCK1/2) are key signalling proteins involved in the regulation of the actin cytoskeleton and control a variety of cellular processes. This includes cell proliferation, stemness, cell migration and invasion as well as actomyosin contraction and extracellular matrix (ECM) remodelling. Due to a lack of ROCK2 specific inhibitors, previous pharmacological studies of ROCK function have relied on pan-ROCK1/2 inhibition. Here, we use the ROCK2 specific inhibitor, GV101, in the context of breast cancer (BC) models to uncouple the effects of ROCK2 pharmacological inhibition on both epithelial and stromal fibroblast cell populations. We demonstrate that ROCK2 inhibition with GV101 reduces fibroblast-mediated remodelling of pre-existing and de novo synthesised ECM resulting in a reduction in biomechanical stiffness, while also limiting epithelial cell growth in 2D and 3D settings. We also demonstrate that ROCK2 inhibition exposes epithelial cell vulnerability to fluid flow-induced shear stress. Furthermore, using 3D co-cultures we reveal that GV101 reduces single-cell migratory capacity, while the disruption of stromal ECM architecture is sufficient to impede collective cell migration and invasion. Finally, we assessed ROCK2 expression in human BC patient tumours revealing that ROCK2 expression is up-regulated during BC progression and that high ROCK2 expression correlates with poor patient outcome in the triple-negative subtype of BC. Together, these results demonstrate that ROCK2 specific inhibition disrupts key functions in both epithelial cell and stromal fibroblast compartments warranting further assessment of ROCK2 in highly proliferative, fibrotic or metastatic diseases, such as BC. HighlightsO_LIFibroblast-mediated remodelling of pre-existing and de novo synthesised extracellular matrix is reduced upon ROCK2 specific targeting. C_LIO_LIROCK2 inhibition impairs epithelial cancer cell growth and colony formation in 2D and 3D contexts, while also limiting single-cell migration and cell survival upon fluid flow-induced shear stress. C_LIO_LIROCK2 targeting during fibroblast-mediated ECM remodelling is sufficient to disrupt collective cell migration as well as 3D invasion into organotypic fibroblast-contracted collagen matrices. C_LIO_LIROCK2 expression is up-regulated during breast cancer progression and high expression correlates with poor patient outcome in triple-negative breast cancer. C_LI

cell biology↗

bioRxiv2025

Activation of PP2A-B56α leads to aberrant EGFR signaling and proliferative phenotypes in PDAC

Pancreatic ductal adenocarcinoma (PDAC) stands to become the second most deadly cancer by 2030. The small GTPase, KRAS, is mutated in over 90% of PDAC patients and considered the primary driver mutation. Despite being an almost ubiquitous event, KRAS mutations have been difficult to target therapeutically, particularly KRASG12D, the most common mutation in PDAC. In addition to these pharmacological challenges, KRAS mutations have been shown to drive signaling plasticity and therapeutic resistance through phosphorylation cascades in most cancers. Protein phosphatases are master regulators of kinase signaling, however the contribution of phosphatase deregulation to mutant KRAS cancer phenotypes is poorly understood. Protein phosphatase 2A (PP2A) inhibits effectors downstream of KRAS, placing this family of enzymes as key regulators of PDAC oncogenic signaling. However, our previous studies utilizing small molecule activating compounds of PP2A show a heterogeneous response in PDAC, with some cell lines displaying increased oncogenic signaling despite induction of phosphatase activity. Similarly, specific PP2A subunits exhibit both tumor suppressive and oncogenic functions depending on the cellular context. Therefore, understanding the role of PP2A in regulating cancer phenotypes is critical for the future development of therapeutic strategies that leverage this phosphatase. Here, we determined the impact of the specific PP2A subunit, B56, on PDAC phenotypes using both genetic and pharmacological activation strategies in human PDAC cell lines and genetic mouse models. We demonstrate that while PP2A-B56 suppresses specific oncogenic pathways, B56 activation exacerbates PDAC proliferative phenotypes and decreases overall survival in vivo, potentially through increased epidermal growth factor receptor (EGFR) signaling. EGFR is a critical signaling node in PDAC as inhibition or loss of EGFR prevents KRAS-driven tumorigenesis and increased EGFR activity is associated with poor patient outcome. The activation of EGFR by PP2A-B56 is in part mediated through increased expression and processing of EGFR ligands, specifically amphiregulin, heparin-binding EGF-like growth factor (HB-EGF), and epiregulin. Furthermore, pharmacological PP2A activation in combination with EGFR inhibitors mitigates this signaling and increases cell death. Together, these studies implicate a previously undescribed non-canonical role for PP2A-B56 in EGFR signaling that contributes to PDAC progression.

cancer biology↗

bioRxiv2025

Skeletal muscle proteomic responses to energy deficit with concomitant aerobic exercise in humans

Energy deficit is a potent physiological stressor that has shaped human evolution and can improve lifespan and healthspan in a wide range of species. Preserving locomotive capacity was likely essential for survival during the human hunter-gatherer period but surprisingly little is known about the molecular effects of energy deficit on human skeletal muscle, which is a key tissue for locomotion and metabolic health. Here we show that a 5-day 78% reduction in energy availability with concomitant aerobic exercise in healthy men leads to a profound modulation of skeletal muscle phenotype alongside increases in fat oxidation at rest and during exercise and a 2.1 {+/-}0.8 kg loss of fat free mass and 0.8 {+/-}0.6 kg of fat mass. We used stable isotope (D2O) labelling and peptide mass spectrometry to investigate the abundance and turnover rates of individual proteins. Abundance (1469 proteins) and synthesis rate (736 proteins) data discovered a shift toward a more oxidative phenotype and reorganisation of cytoskeleton and extracellular matrix structure during energy deficit. Mitochondrial components: TCA, electron transport chain and beta-oxidation, were prominently represented amongst proteins that increased in abundance and synthesis rate, as well as proteins related to mitochondrial proteostasis, remodelling and quality-control such as BDH1 and LONP1. Changes in muscle metabolic pathways occurred alongside a reduction in extracellular matrix proteins, which may counteract the age-related muscle fibrosis. Our results suggest that muscle metabolic pathways are not only preserved but positively affected during periods of concomitant low energy availability and exercise.

physiology↗

bioRxiv2025

Dysproteostasis primes pancreatic epithelial state changes in KRAS-mediated oncogenesis

Pre-malignant transformation of pancreatic acinar cells by oncogenic Kras is dependent upon stochastic emergence of metaplastic cell states, through unknown mechanisms. We reveal that an early, transcriptionally-mediated effect of Kras is sporadic failure of proteostatic ER-phagy. Genetically-altered mice deficient in ER-phagy demonstrate that this event co-operates with Kras to drive acinar-ductal metaplasia (ADM) and subsequent cancer. Mechanistically, proteomics and high-resolution imaging uncover pathologic aggregation of a subset of ER proteins, including the injury marker REG3B, resulting from failure to physically interact with the ER-phagy receptor CCPG1. Spatial transcriptomics demonstrate that the appearance of sporadic intracellular aggregates upon Kras activation marks rare acinar cells existing in an injured, ADM-primed state. Importantly, engineered mutants of REG3B establish that aggregate formation is sufficient to directly engender this epithelial cell state. Pancreatic cancer can thus arise from stochastic pathologic protein aggregates that are influenced by and co-operate with an oncogene.

cancer biology↗

bioRxiv2024

Oncogenic KRAS cells use Wnt signalling and cell dormancy to override homeostatic cell elimination mechanisms in adult pancreas.

Epithelial tissues use homeostatic defence mechanisms to actively expel aberrant or genetically mutant cells and prevent disease. When present in healthy tissues in low numbers, we show that cells expressing cancer-causing mutations (KrasG12D, p53R172H) compete with normal cells for survival and are often eliminated. Thus, tumour initiation must require mechanisms whereby mutant cells override tissue defence mechanisms to remain in a tissue; however, the biology of these initial events is poorly understood. Here, we use an in vivo model of sporadic tumorigenesis in the adult pancreas to show that a population of KrasG12D- or p53R172H-expressing cells are never eliminated from the epithelium. Using RNA sequencing of non-eliminated populations and quantitative fluorescence imaging, we show that {beta}-catenin-independent Wnt5a signalling, and cell dormancy are key features of surviving KrasG12D cells in vivo. We demonstrate that Wnt5a (and not Wnt3a) inhibits apical extrusion of RasV12 cells in vitro by promoting stable E-cadherin-based cell-cell adhesions at RasV12-normal cell-cell boundaries. Inhibition of Wnt5a signalling restores E-cadherin dynamics at normal-mutant boundaries and apical extrusion in vitro. RasV12 cells arrested in the cell cycle are not extruded and this is rescued when Wnt signalling is inhibited. In the pancreas, Wnt signalling, E-cadherin and {beta}-catenin are increased at cell-cell contacts between non-eliminated KrasG12D cells and normal neighbours. Importantly, we demonstrate that active Wnt signalling is a general mechanism required to promote KrasG12D and p53R172H cell survival in vivo. Treatment with porcupine inhibitor rescues pancreas tissue defence by switching mutant cell retention to cell expulsion. Our results suggest that RAS mutant cells activate Wnt and a dormant cell state to avoid cell expulsion and to survive in the adult pancreas.

cell biology↗

bioRxiv2023

KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo

Oncogenic KRAS mutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence of KRAS allelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele in KRAS mutant cancers. However, there is still much debate over the function of wild-type KRAS in tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy of Kras in the context of an intact oncogenic Kras in colorectal cancer. We observe that in the presence of oncogenic Kras, wild-type Kras acts to restrain tumour growth. Mechanistically, deletion of wild-type Kras exacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-type Kras potentiates the oncogenic effect of KRASG12D, while presence of wild-type Kras is associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-type Kras in oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-type Kras during colon tumour initiation and highlights the critical impact of wild-type Kras upon therapeutic response to MAPK and tumour progression in Kras mutant cancers. HighlightsO_LIWild-type KRAS suppresses mutant KRASG12D mediated proliferation and signalling in colorectal cancer models in vivo C_LIO_LIConcomitant loss of wild-type KRAS and activation of WNT signalling promotes mutant KRAS-driven tumour initiation. C_LIO_LIWild-type KRAS promotes resistance to MAPK inhibition in KRAS mutant tumours C_LIO_LILoss of wild-type KRAS inhibits metastasis of late-stage mutant KRAS colorectal cancer models. C_LI

cancer biology↗

bioRxiv2023

Kras loss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity

Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.

cancer biology↗

bioRxiv2023

Human skeletal muscle methylome after low carbohydrate energy balanced exercise

We aimed to investigate the human skeletal muscle (SkM) DNA methylome after exercise in low carbohydrate (CHO) energy balance (with high fat) compared with exercise in low-CHO energy deficit (with low fat) conditions. The objective to identify novel epigenetically regulated genes and pathways associated with train-low sleep-low paradigms. The sleep-low conditions included 9 males that cycled to deplete muscle glycogen while reaching a set energy expenditure. Post-exercise, low-CHO meals (protein-matched) completely replaced (using high-fat) or only partially replaced (low-fat) the energy expended. The following morning resting baseline biopsies were taken and the participants then undertook 75 minutes of cycling exercise, with skeletal muscle biopsies collected 30 minutes and 3.5 hours post exercise. Discovery of genome-wide DNA methylation was undertaken using Illumina EPIC arrays and targeted gene expression analysis was conducted by RT-qPCR. At baseline participants under energy balance (high fat) demonstrated a predominantly hypermethylated (60%) profile across the genome compared to energy deficit-low fat conditions. However, post exercise performed in energy balance (with high fat) elicited a more prominent hypomethylation signature 30 minutes post-exercise in gene regulatory regions important for transcription (CpG islands within promoter regions) compared with exercise in energy deficit (with low fat) conditions. Such hypomethylation was enriched within pathways related to: IL6-JAK-STAT signalling, metabolic processes, p53 / cell cycle and oxidative / fatty acid metabolism. Hypomethylation within the promoter regions of genes: HDAC2, MECR, IGF2 and c13orf16 were associated with significant increases in gene expression in the post-exercise period in energy balance compared with energy deficit. Furthermore, histone deacetylase, HDAC11 was oppositely regulated at the gene expression level compared with HDAC2, where HDAC11 was hypomethylated yet increased in energy deficit compared with energy balance conditions. Overall, we identify some novel epigenetically regulated genes associated with train-low sleep-low paradigms.

physiology↗

bioRxiv2022

βIII-Tubulin is a Brake on Extrinsic Cell-Death in Pancreatic Cancer

The microtubule protein, {beta}III-tubulin, has been implicated as a prognostic, pro-survival, and chemoresistance factor in some of the most lethal malignancies including pancreatic ductal adenocarcinoma (PDAC). However, precise survival mechanisms controlled by {beta}III-tubulin in cancer cells are unknown. Here, we report an unexpected role of {beta}III-tubulin as a brake on extrinsic caspase 8-dependent apoptosis in PDAC. We show that {beta}III-tubulin knockdown frees death-receptor DR5 to increase its membrane diffusion, clustering, and activation of cell-death. We demonstrate that {beta}III-ubulin silencing increases sensitivity of PDAC cells to chemotherapeutic and microenvironment-derived extrinsic cell-death signals including TRAIL, TNF, and FasL. Finally, nanoparticle delivery of {beta}III-tubulin siRNA to mouse orthotopic PDAC tumours in vivo and human patient-derived PDAC tumour explants ex vivo increases extrinsic apoptosis and reduces tumour progression. Thus, silencing of {beta}III-tubulin represents an innovative strategy to unleash a suicide signal in PDAC cells and render them sensitive to microenvironment and chemotherapy-derived death signals.

cancer biology↗

bioRxiv2021

Maturation, developmental site, and pathology dictate murine neutrophil function

Neutrophils have been implicated in poor outcomes in cancer and severe inflammation. We found that neutrophils expressing intermediate levels of Ly6G (Ly6GInt) were present in mouse cancer models and more abundant in those with high rates of spontaneous metastasis. Maturation, age, tissue localization and functional capacity all drive neutrophil heterogeneity. Recent studies have proposed various markers to distinguish between these heterogeneous sub-populations; however, these markers are limited to specific models of inflammation and cancer. Here, we identify and define Ly6G expression level as a robust and reliable marker to distinguish neutrophils at different stages of maturation. Ly6GInt neutrophils were bona fide immature neutrophils with reduced immune regulatory and adhesion capacity. Whereas the bone marrow is a more recognised site of granulopoiesis, the spleen also produces neutrophils in homeostasis and cancer. Strikingly, neutrophils matured faster in the spleen than in the bone marrow with unique transcriptional profiles. We propose that developmental origin is critical in neutrophil identity and postulate that neutrophils that develop in the spleen supplement the bone marrow by providing an intermediate more mature reserve before emergency haematopoiesis.

immunology↗

bioRxiv2020

KRASG12D mutant cells are outcompeted by wild type neighbours in adult pancreas in an EPHA2-dependent manner.

As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbours for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that prior to being cleared, KrasG12D cells lose cell volume, segregate from normal cells and decrease E-cadherin-based cell-cell adhesions with normal neighbours. We identify EphA2 receptor is an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells no longer segregate, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. Retention of KRasG12D cells leads to an increased burden of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumour suppressor in pancreatic cancer.

cell biology↗

bioRxiv2018

The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype.

Cellular senescence is a stress response program characterised by a robust cell cycle arrest and the induction of a pro-inflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumour suppressors p53-p21CIP1, p16INK4a and p15INK4b, and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAA) that, in turn, function as the damage associated molecular patterns (DAMPs) signalling through TLR2 in OIS. Finally, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.

cell biology↗

bioRxiv2018

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by abundant infiltration of tumor associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, the front-line chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Additionally, we report pyrimidine release is a general function of anti-inflammatory myeloid cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

cancer biology↗