Insight into Mantle Cell Lymphoma Pathobiology, Diagnosis, and Treatment Using Network-Based and Drug-Repurposing Approaches

Georgia Orfanoudaki; Konstantina Psatha; Michalis Aivaliotis

doi:10.3390/ijms25137298

Insight into Mantle Cell Lymphoma Pathobiology, Diagnosis, and Treatment Using Network-Based and Drug-Repurposing Approaches

Int J Mol Sci. 2024 Jul 2;25(13):7298. doi: 10.3390/ijms25137298.

Authors

Georgia Orfanoudaki^{1

2}, Konstantina Psatha^{1

2

3}, Michalis Aivaliotis^{1

2

4

5}

Affiliations

¹ Functional Proteomics and Systems Biology (FunPATh), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, GR-54124 Thessaloniki, Greece.
² Institute of Molecular Biology and Biotechnology Foundation for Research and Technology-Hellas, GR-70013 Heraklion, Greece.
³ Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
⁴ Basic and Translational Research Unit, Special Unit for Biomedical Research and Education, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.
⁵ Laboratory of Biological Chemistry, School of Medicine, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece.

Abstract

Mantle cell lymphoma (MCL) is a rare, incurable, and aggressive B-cell non-Hodgkin lymphoma (NHL). Early MCL diagnosis and treatment is critical and puzzling due to inter/intra-tumoral heterogeneity and limited understanding of the underlying molecular mechanisms. We developed and applied a multifaceted analysis of selected publicly available transcriptomic data of well-defined MCL stages, integrating network-based methods for pathway enrichment analysis, co-expression module alignment, drug repurposing, and prediction of effective drug combinations. We demonstrate the "butterfly effect" emerging from a small set of initially differentially expressed genes, rapidly expanding into numerous deregulated cellular processes, signaling pathways, and core machineries as MCL becomes aggressive. We explore pathogenicity-related signaling circuits by detecting common co-expression modules in MCL stages, pointing out, among others, the role of VEGFA and SPARC proteins in MCL progression and recommend further study of precise drug combinations. Our findings highlight the benefit that can be leveraged by such an approach for better understanding pathobiology and identifying high-priority novel diagnostic and prognostic biomarkers, drug targets, and efficacious combination therapies against MCL that should be further validated for their clinical impact.

Keywords: biomarkers; differentially expressed; drug repurposing; mantle cell lymphoma; non-Hodgkin lymphoma; stages.

MeSH terms

Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Biomarkers, Tumor / metabolism
Drug Repositioning* / methods
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic / drug effects
Gene Regulatory Networks / drug effects
Humans
Lymphoma, Mantle-Cell* / diagnosis
Lymphoma, Mantle-Cell* / drug therapy
Lymphoma, Mantle-Cell* / genetics
Lymphoma, Mantle-Cell* / metabolism
Lymphoma, Mantle-Cell* / pathology
Osteonectin / genetics
Osteonectin / metabolism
Signal Transduction / drug effects
Transcriptome
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism

Substances

Osteonectin
Vascular Endothelial Growth Factor A
SPARC protein, human
Biomarkers, Tumor
VEGFA protein, human
Antineoplastic Agents

Grants and funding

This research was funded by the project Advanced Research Activities in Biomedical and Agro-alimentary Technologies (MIS 5002469) which is implemented under the Action for the Strategic Development on the Research and Technological Sector, funded by the operational program Competitiveness, Entrepreneurship and Innovation (NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund). Konstantina Psatha was funded by a Stavros Niarchos Foundation—FORTH Fellowship for postdoctoral researchers within the framework of the project ARCHERS. The research is co-financed by Greece and the European Union (European Social Fund—ESF) through the operational program Human Resources Development, Education and Lifelong Learning in the context of the project Reinforcement of Postdoctoral Researchers—2nd Cycle (MIS-5033021), implemented by the State Scholarships Foundation (ΙΚY).