Biology subjects

Conley, P.

Publications and source records attributed to Conley, P..

4 recordsLinked to original sources

bioRxiv2023

Analysis of uveal melanoma scRNA sequencing data identifies neoplastic-immune hybrid cells that exhibit metastatic potential

Uveal melanoma (UM) is the most common non-cutaneous melanoma and is an intraocular malignancy that affects nearly 7,000 individuals per year worldwide. Of these, nearly 50% will progress to metastatic disease for which there are currently no effective therapies. Despite advances in the molecular profiling and metastatic stratification of class 1 and 2 UM tumors, little is known regarding the underlying biology of UM metastasis. Our group has identified a disseminated tumor cell population characterized by co-expression of immune and melanoma proteins, (circulating hybrid cells (CHCs), in patients with UM. Compared to circulating tumor cells, CHCs are detected at an increased prevalence in peripheral blood and can be used as a non-invasive biomarker to predict metastatic progression. To identify mechanisms underlying enhanced hybrid cell dissemination we sought to identify hybrid cells within a primary UM single cell RNA-seq dataset. Using rigorous doublet discrimination approaches, we identified UM hybrids and evaluated their gene expression, predicted ligand-receptor status, and cell-cell communication state in relation to other melanoma and immune cells within the primary tumor. We identified several genes and pathways upregulated in hybrid cells, including those involved in enhancing cell motility and cytoskeleton rearrangement, evading immune detection, and altering cellular metabolism. In addition, we identified that hybrid cells express ligand-receptor signaling pathways implicated in promoting cancer metastasis including IGF1-IGFR1, GAS6-AXL, LGALS9-P4HB, APP-CD74 and CXCL12-CXCR4. These results contribute to our understanding of tumor progression and interactions between tumor cells and immune cells in the UM microenvironment that may promote metastasis.

cancer biology↗

bioRxiv2023

Pathway-based, reaction-specific annotation of disease variants for elucidation of molecular phenotypes

Disease variant annotation in the context of biological reactions and pathways can provide a standardized overview of molecular phenotypes of pathogenic mutations that is amenable to computational mining and mathematical modeling. Reactome, an open source, manually curated, peer-reviewed database of human biological pathways, provides annotations for over 4000 disease variants of close to 400 genes in the context of [~]800 disease reactions constituting [~]400 disease pathways. Functional annotation of disease variants proceeds from normal gene functions, through disease variants whose divergence from normal molecular behaviors has been experimentally verified, to extrapolation from molecular phenotypes of characterized variants to variants of unknown significance using criteria of the American College of Medical Genetics and Genomics (ACMG). Reactomes pathway-based, reaction-specific disease variant dataset and data model provide a platform to infer pathway output impacts of numerous human disease variants and model organism orthologs, complementing computational predictions of variant pathogenicity.

systems biology↗

bioRxiv2023

Illuminating Dark Proteins using Reactome Pathways

Limited knowledge about a substantial portion of protein coding genes, known as "dark" proteins, hinders our understanding of their functions and potential therapeutic applications. To address this, we leveraged Reactome, the most comprehensive, open source, open-access pathway knowledgebase, to contextualize dark proteins within biological pathways. By integrating multiple resources and employing a random forest classifier trained on 106 protein/gene pairwise features, we predicted functional interactions between dark proteins and Reactome-annotated proteins. We then developed three scores to measure the interactions between dark proteins and Reactome pathways, utilizing enrichment analysis and fuzzy logic simulations. Correlation analysis of these scores with an independent single-cell RNA sequencing dataset provided supporting evidence for this approach. Furthermore, systematic natural language processing (NLP) analysis of over 22 million PubMed abstracts and manual checking of the literature associated with 20 randomly selected dark proteins reinforced the predicted interactions between proteins and pathways. To enhance the visualization and exploration of dark proteins within Reactome pathways, we developed the Reactome IDG portal, deployed at https://idg.reactome.org, a web application featuring tissue-specific protein and gene expression overlay, as well as drug interactions. Our integrated computational approach, together with the user-friendly web platform, offers a valuable resource for uncovering potential biological functions and therapeutic implications of dark proteins.

bioinformatics↗

bioRxiv2022

Dual states of Bmi1-expressing intestinal stem cells drive epithelial development and tissue regeneration

Intestinal development, response to injury and disease states rely upon balanced stem cell proliferation. Historically, two subtypes of intestinal epithelial stem cells (ISCs)--slow-cycling/label-retaining, and actively-cycling/canonical Wnt-dependent--coordinate to drive proliferation and regulate epithelial renewal during adult tissue homeostasis and injury response. Recent studies focused on Bmi1-expressing cells revealed that differentiated Bmi1+ enteroendocrine cells could dedifferentiate towards a canonical Wnt-dependent stem cell state, calling into question the dogma that a dual stem cell axis regulates epithelial proliferation. Herein, we identify stem cell function in a Bmi1+ cell population in early murine intestinal development prior to the establishment of canonical Wnt-dependent, Lgr5-expressing ISCs. In-depth analyses of developmental Bmi1+ ISCs using lineage-tracing and single cell RNA-sequencing reveal their distinct identity and capacity to differentiate into Lgr5+ ISCs and other differentiated lineages. Further, during in utero development, the Bmi1+ ISCs initially exists in a highly proliferative state then transitions to a slow-cycling state, with the emergence of actively-cycling Lgr5+ ISCs. In adult tissue, Bmi1+ ISCs are a distinct population that re-express developmental gene and protein profiles, and a non-canonical Wnt signaling signature in response to injury and in human colorectal tumors. Further, developmental Bmi1+ ISCs are distinct from Lgr5+ ISCs and the previously identified differentiated Bmi1+ progenitor cells. Re-evaluation of an under-appreciated Bmi1+ ISC population with fundamental importance in intestinal development re-establishes the importance of the dynamic interplay between discrete ISC populations that are regulated by opposing Wnt signaling pathways. This finding opens opportunities and targetable pathways to augment regeneration or inhibit tumorigenesis.

developmental biology↗