Biology subjects

Ignatchenko, V.

Publications and source records attributed to Ignatchenko, V..

5 recordsLinked to original sources

bioRxiv2025

Surface proteomics reveals arginine metabolism as a vulnerability in high grade serous ovarian cancer

The significant lethality of high-grade serous ovarian cancer (HGSC) is driven by the lack of long-term efficacy of current treatments, underscoring the need for developing additional therapeutics. Cell surface proteins represent attractive therapeutic targets yet remain underexplored in high-grade serous ovarian cancer. Here, we employed cell surface N-glycoproteomics to elucidate the cell surface proteomes of HGSC cells alongside normal epithelial and cancer-associated stromal cells, uncovering new opportunities for therapeutic intervention. Integration of cell surface N-glycoproteomics and functional screening revealed multiple minimally characterized, HGSC-enriched surface proteins that are critical for HGSC proliferation, most notably, SLC7A1. Multi-omic and functional characterization indicated that SLC7A1 is necessary for HGSC migration, protein synthesis and mitochondrial functions likely linked to its role as an arginine transporter. Finally, we demonstrate that elevated surface expression of SLC7A1 in HGSC reflects dysregulated arginine metabolism, pointing to a putative therapeutic vulnerability. Our work identifies SLC7A1 and arginine metabolism as a previously unrecognized molecular vulnerability in HGSC and provides a framework to guide future therapeutic development.

cancer biology↗

bioRxiv2024

Pan-cancer N-glycoproteomic atlas of patient derived xenografts uncovers FAT2 as a therapeutic target for head and neck cancers

Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central role in cellular signaling. Despite this, their promise remains largely untapped due to the technical challenges inherent to profiling cell surface proteins. Here, we employed N-glycoproteomics to analyze 85 patient-derived xenografts (PDX), constructing Glyco PDXplorer - an in vivo pan-cancer atlas of cancer-derived cell surface proteins. We developed a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validated FAT2 as a head and neck squamous cancer (HNSC) enriched surface protein with limited expression in normal tissue. Functional studies revealed that FAT2 is essential for HNSC growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR) T cells targeting FAT2 demonstrated potent anti-tumor activity in HNSC models. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal resource to inform therapeutic target discovery for multiple cancers. HIGHLIGHTSO_LIPan-cancer landscape of cancer-derived cell surface proteins detected in vivo C_LIO_LIDevelopment of a multi-omic discovery pipeline to prioritize proteins with optimal expression profiles as immunotherapy targets C_LIO_LIIdentification and validation of FAT2 as a head and neck squamous cancer enriched surface protein with minimal expression in normal tissues C_LIO_LIFAT2 coordinates cell surface organization, adhesion, growth and survival through the integrin-PI3K-AKT pathway C_LIO_LIFAT2 CAR T cells demonstrate anti-tumour activity in pre-clinical models C_LI

cancer biology↗

bioRxiv2023

Prostate Cancer Reshapes the Secreted and Extracellular Vesicle Urinary Proteomes

Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions, and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome, and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.

systems biology↗

bioRxiv2022

Glycoproteomics Identifies Plexin-B3 as Targetable Cell Surface Protein Required for Growth and Invasion of Triple Negative Breast Cancer Cells

Driven by the lack of targeted therapies, triple negative breast cancers (TNBC) have the worst overall survival of all breast cancer subtypes. Considering cell surface proteins are favorable drug targets and are predominantly glycosylated, glycoproteome profiling has significant potential to facilitate the identification of much-needed drug targets for TNBC. Here, we performed N-glycoproteomics on six TNBC and five normal control (NC) cell lines using hydrazide-based enrichment. Quantitative proteomics and integrative data mining led to the discovery of Plexin-B3 (PLXNB3), a previously undescribed TNBC-enriched cell surface protein. Furthermore, siRNA knock-down and CRISPR-Cas9 editing of in vitro and in vivo models show that PLXNB3 is required for TNBC cell line growth, invasion, and migration. Altogether, we provide insight into N-glycoproteome remodeling associated with TNBC and functional evaluation of an extracted target, which indicate the surface protein PLXNB3 as a potential therapeutic target for TNBC. HighlightsO_LIIn-depth N-glycoproteomic profiles of six TNBC and five NC cell line models C_LIO_LIIdentification of PLXNB3 as a novel TNBC-enriched cell surface protein C_LIO_LIPLXNB3 affects growth, invasion, and migration in TNBC models C_LIO_LIPLXNB3 inhibition represents a targeted treatment option for TNBC C_LI

cancer biology↗

bioRxiv2019

Mammary epithelial cells have lineage-restricted metabolic identities

Cancer metabolism adapts the metabolic network of its tissue-of-origin. However, breast cancer is not a disease of a singular origin. Multiple epithelial populations serve as the culprit cell-of-origin for specific breast cancer subtypes, yet knowledge surrounding the metabolic network of normal mammary epithelial cells is limited. Here, we show that mammary populations have cell type-specific metabolic programs. Primary human breast cell proteomes of basal, luminal progenitor, and mature luminal populations revealed their unique enrichment of metabolic proteins. Luminal progenitors had higher abundance of electron transport chain subunits and capacity for oxidative phosphorylation, whereas basal cells were more glycolytic. Targeting oxidative phosphorylation and glycolysis with inhibitors exposed distinct metabolic vulnerabilities of the mammary lineages. Computational analysis indicated that breast cancer subtypes retain metabolic features of their putative cell-of-origin. Lineage-restricted metabolic identities of normal mammary cells partly explain breast cancer metabolic heterogeneity and rationalize targeting subtype-specific metabolic vulnerabilities to advance breast cancer therapy.

cell biology↗