Biology subjects

Peterson, N.

Publications and source records attributed to Peterson, N..

8 recordsLinked to original sources

bioRxiv2026

Contact-dependent growth inhibition drives kin discrimination and shapes in vivo strain dominance in Pseudomonas aeruginosa infection

Pseudomonas aeruginosa is a ubiquitous environmental bacterium and an opportunistic pathogen. Rather than existing as single clonal lineages, environmental and clinical populations often consist of a mixture of distinct strains that directly compete to dominate the niche. To eliminate rivals, P. aeruginosa deploys a form of interference competition termed contact-dependent growth inhibition (CDI). CDI is mediated by CdiA, where, upon cell contact, the CdiA C-terminal toxin domain is delivered to prey cells. Toxin-producing cells encode for a cognate CdiI immunity protein to prevent self-intoxication. Different strains of P. aeruginosa encode for CdiA proteins with different C-terminal toxin domains and cognate CdiI immunity proteins. Most studies have relied on engineered strains to investigate the mechanism of CDI. While extremely useful for studying CdiA-mediated intoxication, such work masks the true diversity of wild-type CdiA variants and their impact on competitive interactions between strains. In this study, we systematically investigated CDI-mediated competition using unique conspecific strains of P. aeruginosa. We identified several novel CdiA toxin domains and mapped the competitive outcomes they govern. Furthermore, using a mouse model of acute pneumonia, we demonstrate that CDI-mediated interference competition actively occurs during mixed-strain infections in vivo. Together, our findings reveal that P. aeruginosa leverages CDI as a potent, strain-dependent kin discrimination mechanism that directly shapes population dynamics and strain dominance within host and natural environments.

microbiology↗

bioRxiv2025

Longitudinal Analysis of Matched Patient Biospecimens Reveals Neural Reprogramming of Cancer-Associated Fibroblasts Following Chemotherapy in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer, is a deadly disease with a complex tumor microenvironment (TME). How chemotherapy alters the TME, and whether these changes drive chemoresistance, is poorly understood. We examined matched pre- and post-treatment tissue specimens and found near-universal enrichment of axonal guidance genes in cancer-associated fibroblasts (CAFs) after treatment. These CAFs were enriched near sites of perineural invasion, coinciding with regions of increased tumor cell proliferation, and were enriched in tumor areas distant from nerves after chemotherapy. Metastatic recurrence lesions had the highest prevalence of these CAFs versus primary tumors and untreated metastasis. These CAFs showed elevated non-canonical Wnt mediators and axonal guidance genes, which complemented matching cognate binding partners in tumor epithelial cells, suggesting a role in tumor-stroma crosstalk. Our findings implicate fibroblast-derived axonal-guidance genes in promoting PDAC invasion and point to a promising target for this disease. Statement of SignificanceTherapeutic resistance remains a major challenge in pancreatic cancer. Our findings shed light on the changes in the complex tumor microenvironment in response to chemotherapy and identify fibroblasts high in axonal-guidance genes that may drive tumor progression and chemoresistance, thus uncovering a potential avenue for targeting pancreatic cancer.

cancer biology↗

bioRxiv2025

Spatial analysis of IPMNs defines a paradoxical KRT17-positive, low-grade epithelial population harboring malignant features

Background & AimsIntraductal papillary mucinous neoplasms (IPMNs) are pancreatic cysts that represent one of the few radiologically identifiable precursors to pancreatic ductal adenocarcinoma (PDAC). Though the IPMN-bearing patient population represents a unique opportunity for early detection and interception, current guidelines provide insufficient accuracy in determining which patients should undergo resection versus surveillance, resulting in a sizable fraction of resected IPMNs only harboring low-grade dysplasia, suggesting that there may be overtreatment of this clinical entity. MethodsTo investigate the transcriptional changes that occur during IPMN progression, we performed spatial transcriptomics using the Nanostring GeoMx on patient samples containing the entire spectrum of IPMN disease including low-grade dysplasia, high-grade dysplasia, and IPMN-derived carcinoma. Single cell RNA sequencing was performed on side branch and main duct IPMN biospecimens. ResultsWe identified a subpopulation of histologically low-grade IPMN epithelial cells that express malignant transcriptional features including KRT17, S100A10 and CEACAM5, markers that are enriched in PDAC. We validated this high-risk gene signature in both single-cell RNA sequenced samples and an external ST dataset containing a larger number of IPMN samples including non-tumor bearing IPMN (i.e. low-grade IPMN in isolation). Immunofluorescence staining of a large cohort of patient tissues confirmed the presence of KRT17-positive cells, which were found to comprise a small subset of epithelial cells within histologically low-grade IPMN in a patchy distribution. ConclusionsOur study demonstrates that KRT17 marks a distinct transcriptional signature in a subpopulation of epithelial cells within histologically low-grade IPMN. This population of cells likely represents a transitional state of histologically low-grade epithelial cells undergoing progression to a higher grade of dysplasia and thus may represent a higher risk of progression to carcinoma. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/643943v2_ufig1.gif" ALT="Figure 1000"> View larger version (43K): org.highwire.dtl.DTLVardef@47d380org.highwire.dtl.DTLVardef@18e7ab2org.highwire.dtl.DTLVardef@1193ffeorg.highwire.dtl.DTLVardef@b84a98_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

cancer biology↗

bioRxiv2025

Synaptic vesicle glycoprotein 2 enables viable aneuploidy following centrosome amplification

Amplified centrosome number causes genomic instability, most severely through division into more than two aneuploid daughter cells (multipolar mitosis). Several mechanisms that suppress multipolar division have been uncovered, yet mechanisms that favor viable multipolar division are poorly understood. To uncover factors that promote viability in cells with frequent centrosome amplification and multipolar division, we conducted an unbiased Drosophila genetic screen. In 642 mutagenized lines, we exploited the ability of intestinal papillar cells to form and function despite multipolar divisions. Our top hit is an unnamed gene, CG3168. We name this gene synaptic vesicle glycoprotein 2, reflecting homology to human Synaptic Vesicle Glycoprotein 2 (SV2) proteins. GFP-tagged SV2 localizes to the plasma membrane. In cells with amplified centrosomes, SV2 positions membrane-adjacent centrosomes, which prevents severe errors in chromosome alignment and segregation. Our results uncover membrane-based multipolar division regulation and reveal a novel vulnerability in cells with common cancer properties.

cell biology↗

bioRxiv2023

Conserved Chamber-Specific Polyploidy Maintains Heart Function in Drosophila

Developmentally programmed polyploidy (whole-genome-duplication) of cardiomyocytes is common across evolution. Functions of such polyploidy are essentially unknown. Here, we reveal roles for precise polyploidy levels in cardiac tissue. We highlight a conserved asymmetry in polyploidy level between cardiac chambers in Drosophila larvae and humans. In Drosophila, differential Insulin Receptor (InR) sensitivity leads the heart chamber to reach a higher ploidy/cell size relative to the aorta chamber. Cardiac ploidy-reduced animals exhibit reduced heart chamber size, stroke volume, cardiac output, and acceleration of circulating hemocytes. These Drosophila phenotypes mimic systemic human heart failure. Using human donor hearts, we reveal asymmetry in nuclear volume (ploidy) and insulin signaling between the left ventricle and atrium. Our results identify productive and likely conserved roles for polyploidy in cardiac chambers and suggest precise ploidy levels sculpt many developing tissues. These findings of productive cardiomyocyte polyploidy impact efforts to block developmental polyploidy to improve heart injury recovery.

developmental biology↗

bioRxiv2023

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions

The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Statement of significanceThe causes underlying the onset of pancreatic cancer remain largely unknown, hampering early detection and prevention strategies. Here, we show that PanIN are abundant in healthy individuals and present at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell intrinsic factors that restrain, or, conversely, promote, malignant progression.

cancer biology↗

bioRxiv2021

Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms

Biguanides, including the worlds most commonly prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. In spite of this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in C. elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor Nrf2/skn-1. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.

genetics↗

bioRxiv2019

Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer.

Poor response to platinum/taxane-based chemotherapy has remained a major hurdle in the management of high grade serous carcinoma of the ovary (HGSC). Recurrent HGSC is often treated with liposomal doxorubicin as a second line chemotherapy. Unfortunately, HGSC patients have not benefited from immunotherapies targeting the PD-1/PD-L1 immune checkpoint axis. In a pre-clinical study evaluating the efficacy of a \"Stimulator of Interferon Genes\" (STING) agonist, we demonstrated the synergistic potential of STING pathway activation in enhancing response to carboplatin chemotherapy and sensitization to PD-1 immune checkpoint blockade (ICB). Since carboplatin and doxorubicin exhibit distinct immunogenic cell death (ICD) inducing potential, we investigated the chemotherapy specific effect in the magnitude of response to exogenous STING pathway activation. Immunocompetent C57/BL6 mice were implanted with ID8-Trp53-/- cells followed by treatment with carboplatin or doxorubicin. Towards rationalized addition of STING agonist with or without PD-L1 blockade, we first determined the expression of 60 known ICD associated genes at an early time point following the initial treatment with carboplatin or doxorubicin with or without STING agonist. Doxorubicin treated tumours showed significantly higher expression of ICD genes, Cxcl10, Cd274, Isg15, Psmb9 and Calr. Expression changes were further amplified following the addition of STING agonist. Significantly higher expression of Cxcl10 and Isg15 were observed in the doxorubicin + STING agonist treated mice compared to carboplatin + STING agonist combination. Interestingly, Ccl5 gene expression was higher in the tumours from carboplatin or carboplatin and STING agonist combination treated mice compared to those treated with doxorubicin. Plasma cytokine analysis showed distinct profiles of CXCL10, CCL5, MCP-1 and IL6 post treatment with each chemotherapy type. Doxorubicin monotherapy treated mice showed significantly longer overall survival compared to their carboplatin counterparts with further increases following addition of either STING agonist or PD-L1 ICB. However, despite the stronger ICD inducing ability of doxorubicin, overall survival of mice treated with carboplatin + STING agonist + PD-L1 ICB was the longest. Findings from our pre-clinical study provide novel insights for rationalized combinations of immune sensitizing agents such as STING pathway activators to improve response of HGSC patients to chemotherapy and ICB in the primary and recurrent settings.

cancer biology↗