Biology subjects

Sundberg, J. P.

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

7 recordsLinked to original sources

bioRxiv2024

Invasive cancer and spontaneous regression two weeks after papillomavirus infection

Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans - the throat, anus, and skin - and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression. Summary Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/611275v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1da9642org.highwire.dtl.DTLVardef@1bef109org.highwire.dtl.DTLVardef@c2ba0eorg.highwire.dtl.DTLVardef@451baf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Seven naturally variant loci serve as genetic modifiers of Lamc2jeb induced non-Herlitz Junctional Epidermolysis Bullosa in mice

Epidermolysis Bullosa (EB) is a group of rare genetic disorders that compromise the structural integrity of the skin such that blisters and subsequent erosions occur after minor trauma. While primary genetic risk of all subforms of EB adhere to Mendelian patterns of inheritance, their clinical presentations and severities can vary greatly, implying genetic modifiers. The Lamc2jeb mouse model of non-Herlitz junctional EB (JEB-nH) demonstrated that genetic modifiers can contribute substantially to the phenotypic variability of JEB and likely other forms of EB. The innocuous changes in an EB related gene, Col17a1, have shown it to be a dominant modifier of Lamc2jeb. This work identifies six additional Quantitative Trait Loci (QTL) that modify disease in Lamc2jeb/jeb mice. Three QTL include other known EB related genes, with the strongest modifier effect mapping to a region including the epidermal hemi-desmosomal structural gene dystonin (Dst-e/Bpag1-e). Three other QTL map to intervals devoid of known EB-associated genes. Of these, one contains the nuclear receptor coactivator Ppargc1a as its primary candidate and the others contain related genes Pparg and Igf1, suggesting modifier pathways. These results, demonstrating the potent disease modifying effects of normally innocuous genetic variants, greatly expand the landscape of genetic modifiers of EB and therapeutic approaches that may be applied.

genetics↗

bioRxiv2023

Microbiome modulates immunotherapy response in cutaneous squamous cell carcinoma

The gut microbiome is increasingly recognized to alter cancer risk, progression, and response to treatments such as immunotherapy, especially in cutaneous melanoma. However, whether the microbiome influences immune checkpoint inhibitor (ICI) immunotherapy response to non-melanoma skin cancer has not yet been defined. As squamous cell carcinomas (SCC) are in closest proximity to the skin microbiome, we hypothesized that the skin microbiome, which regulates cutaneous immunity, might affect SCC-associated anti-PD1 immunotherapy treatment response. We used ultraviolet radiation to induce SCC in SKH1 hairless mice. We then treated the mice with broad-band antibiotics to deplete the microbiome, followed by colonization by candidate skin and gut bacteria or persistent antibiotic treatment, all in parallel with ICI treatment. We longitudinally monitored skin and gut microbiome dynamics by 16S rRNA gene sequencing, and tumor burden by periodic tumor measurements and histologic assessment. Our study revealed that antibiotics-induced abrogation of the microbiome reduced tumor burden, suggesting a functional role of the microbiome in non-melanoma skin cancer therapy response.

microbiology↗

bioRxiv2020

Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death

SHARPIN, together with RNF31/HOIP and RBCK1/HOIL1, form the linear ubiquitin chain assembly complex (LUBAC) E3 ligase that catalyzes M1-linked poly-ubiquitination. Mutations in RNF31/HOIP and RBCK/HOIL1 in humans and Sharpin in mice lead to auto-inflammation and immunodeficiency but the mechanism underlying the immune dysregulation remains unclear. We now show that the phenotype of the Sharpin-/- mice is dependent on CYLD, the deubiquitinase that removes K63-linked poly-ubiquitin chains. The dermatitis, disrupted splenic architecture, and loss of Peyers patches in the Sharpin-/- mice were fully reversed in Sharpin-/-Cyld-/- mice. There is enhanced association of RIPK1 with the death-inducing signaling complex (DISC) following TNF stimulation in Sharpin-/- cells, and this is dependent on CYLD since it is reversed in Sharpin-/-Cyld-/- cells. Enhanced RIPK1 recruitment to the DISC in Sharpin-/- cells correlated with impaired phosphorylation of CYLD at serine 418, a modification reported to inhibit its enzymatic activity. The dermatitis in the Sharpin-/- mice was also ameliorated by the conditional deletion of Cyld using LysM-cre or Cx3cr1-cre indicating that CYLD-dependent death of myeloid cells is inflammatory. Our studies reveal that under physiological conditions, TNF- and RIPK1-dependent cell death is suppressed by the linear ubiquitin-dependent inhibition of CYLD. The Sharpin-/- phenotype illustrates the pathological consequences when CYLD inhibition fails. Short SummaryIn the absence of SHARPIN, cells fail to properly regulate the deubiquitinase CYLD, leading to RIPK1-mediated cell death. Deletion of Cyld reverses the sensitivity of Sharpin-/- cells to TNF-induced cell death, as well as the multi-organ inflammation and immune dysfunction observed in Sharpin-/- mice.

immunology↗

bioRxiv2019

Ankylosis homologue (ANKH) controls extracellular citrate and pyrophosphate homeostasis and affects bone mechanical performance

The membrane protein Ankylosis homologue (ANKH, mouse orthologue: ANK) prevents mineralization of joint-space and articular cartilage. The accepted view is that ANKH mediates cellular release of inorganic pyrophosphate (PPi), a strong physiological inhibitor of mineralization. Using global metabolite profiling, we identified citrate as the most prominent metabolite leaving HEK293 cells in an ANKH-dependent manner. Although PPi levels were increased in culture medium of HEK293-ANKH cells, PPi was formed extracellularly after release of ATP and other nucleoside triphosphates. Ankank/ank mice, which lack functional ANK, had substantially reduced concentrations of citrate in plasma and urine, while citrate was undetectable in urine of a human patient lacking functional ANKH. Bone hydroxyapatite of Ankank/ank mice also contained markedly reduced levels of citrate and PPi and displayed diminished strength. Together, our data show that ANKH is a crucial factor in extracellular citrate and PPi homeostasis that is essential for normal bone development.

developmental biology↗

bioRxiv2018

Mouse Genome-Wide Association and Systems Genetics Identifies Lhfp as a Regulator of Bone Mass

Bone mineral density (BMD) is a strong predictor of osteoporotic fracture. It is also one of the most heritable disease-associated quantitative traits. As a result, there has been considerable effort focused on dissecting its genetic basis. Here, we performed a genome-wide association study (GWAS) in a panel of inbred strains to identify associations influencing BMD. This analysis identified a significant (P=3.1 x 10-12) BMD locus on Chromosome 3@52.5 Mbp that replicated in two seperate inbred strain panels and overlapped a BMD quantitative trait locus (QTL) previously identified in a F2 intercross. The association mapped to a 300 Kbp region containing four genes; Gm2447, Gm20750, Cog6, and Lhfp. Further analysis found that Lipoma HMGIC Fusion Partner (Lhfp) was highly expressed in bone and osteoblasts and its expression was regulated by local expression QTL (eQTL) in multiple tissues. A co-expression network analysis revealed that Lhfp was strongly connected to genes involved in osteoblast differentiation. To directly evaluate its role in bone, Lhfp deficient mice (Lhfp-/-) were created using CRISPR/Cas9. Consistent with genetic and network predictions, bone marrow stromal cells (BMSCs) from Lhfp-/- displayed increased osteogenic differentiation. Lfhp-/- mice also had elevated BMD due to increased cortical bone mass. In conclusion, we used GWAS and systems genetics in mice to identify Lhfp as a regulator of osteoblast activity and bone mass.

genetics↗

bioRxiv2018

Quantitative evaluation of ontology design patterns for combining pathology and anatomy ontologies

Data are increasingly annotated with multiple ontologies to capture rich information about the features of the subject under investigation. Analysis may be performed over each ontology separately, but, recently, there has been a move to combine multiple ontologies to provide more powerful analytical possibilities. However, it is often not clear how to combine ontologies or how to assess or evaluate the potential design patterns available. Here we use a large and well-characterized dataset of anatomic pathology descriptions from a major study of aging mice. We show how different design patterns based on the MPATH and MA ontologies provide orthogonal axes of analysis, and perform differently in over-representation and semantic similarity applications. We discuss how such a data-driven approach might be used generally to generate and evaluate ontology design patterns.

bioinformatics↗