Biology subjects

Evans, J. M.

Publications and source records attributed to Evans, J. M..

4 recordsLinked to original sources

bioRxiv2026

A multi-modal transcriptomic atlas reveals the cellular and spatial landscape of canine gastric cancer

Gastric cancer is the fifth leading cause of cancer-related mortality in humans globally and remains a clinical challenge with limited treatment options and poor survival. Dogs develop spontaneous gastric cancer that parallels the clinical presentation and histology of human disease, supporting their value as a comparative oncology model. Here we present a comprehensive transcriptomic characterization of canine gastric cancer through single-nucleus RNA-sequencing, bulk RNA-sequencing, and Visium HD 3' spatial transcriptomics of treatment-naive tumor and normal stomach tissues from Belgian Tervuren and Belgian Sheepdogs. Across 107,085 nuclei, we identified 44 distinct cell populations, including tumor-enriched states as well as profound depletion of the normal parietal and chief cell gastric lineages. Cell-cell communication analysis revealed enhanced epithelial-fibroblast crosstalk driving epithelial-mesenchymal transition. Bulk RNA-sequencing further identified enrichment of signaling pathways implicated in H. pylori associated human gastric carcinogenesis, including Hippo, PI3K-Akt, and Wnt. Notably, we observed cell-type-specific altered expression of KLHL29, PDZRN3, and PLAU, which are among our previously identified canine gastric cancer susceptibility genes, linking germline risk to specific tumor cellular contexts. These data establish the first transcriptomic atlas of canine gastric cancer and demonstrate substantial molecular homology between canine and human disease.

genomics↗

bioRxiv2024

Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer

Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3, that have not been associated with human GC.

genomics↗

bioRxiv2021

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds

Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart affects flat-coated retrievers (FCRs) at unusually high frequency, with 20% developing the lethal disease. The similar clinical presentation combined with the closed population structure of dogs, leading to high genetic homogeneity, makes dogs an excellent model for genetic studies of cancer susceptibility. To determine the genetic risk factors underlying histiocytic sarcoma in FCRs, we conducted multiple genome-wide association studies (GWASs), identifying two loci that confer significant risk on canine chromosomes (CFA) 5 (Pwald=4.83x10-9) and 19 (Pwald=2.25x10-7). We subsequently undertook a multi-omics approach that has been largely unexplored in the canine model to interrogate these regions, generating whole genome, transcriptome, and chromatin immunoprecipitation sequencing. These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding. The CFA5 association colocalizes with susceptibility loci for two hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, revealing the risk contribution this single locus makes to multiple hematological cancers. By comparison, the CFA19 locus is unique to the FCR and harbors risk alleles associated with upregulation of TNFAIP6, which itself affects cell migration and metastasis. Together, these loci explain ~35% of disease risk, an exceptionally high value that demonstrates the advantages of domestic dogs for complex trait mapping and genetic studies of cancer susceptibility.

genetics↗

bioRxiv2019

Patient-specific functional genomics and disease modeling suggest a role for LRP2 in Hypoplastic Left Heart Syndrome

Congenital heart diseases (CHD), such as hypoplastic left heart syndrome (HLHS), are considered to have complex genetic underpinnings that are poorly understood. Here, an integrated multi-disciplinary approach was applied to identify novel genes and underlying mechanisms associated with HLHS. A family-based strategy was employed that coupled whole genome sequencing (WGS) with RNA sequencing of patient-derived induced pluripotent stem cells (iPSCs) from a sporadic HLHS proband-parent trio to identify, prioritize and functionally evaluate candidate genes in model systems. Consistent with the hypoplastic phenotype, the probands iPSCs had reduced proliferation capacity. Filtering WGS for rare de novo, recessive, and loss-of-function variants revealed 10 candidate genes with recessive variants and altered expression compared to the parents iPSCs. siRNA/RNAi-mediated knockdown in generic human iPSC-derived cardiac progenitors and in the in vivo Drosophila heart model revealed that LDL receptor related protein LRP2 and apolipoprotein APOB are required for robust hiPSC-derived cardiomyocyte proliferation and normal hear structure and function, possibly involving an oligogenic mechanism via growth-promoting WNT and SHH signaling. LRP2 was further validated as a CHD gene in a zebrafish heart model and rare variant burden testing in an HLHS cohort. Collectively, this cross-functional genetic approach to complex congenital heart disease revealed LRP2 dysfunction as a likely novel genetic driver of HLHS, and hereby established a scalable approach to decipher the oligogenic underpinnings of maladaptive left heart development. One sentence summaryWhole genome sequencing and a multi-model system candidate gene validation - human iPSC-derived cardiomyocytes and Drosophila and zebrafish hearts - identified lipoprotein LRP2 as a new potential driver in congenital heart disease and suggests a deficit in proliferation as a hallmark of hypoplastic left heart syndrome.

genetics↗