Community-based network analyses reveal emerging connectivity patterns of protein-protein interactions in murine melanoma secretome

Author(s):Show less -

Francisquini, Rodrigo ^[1] ; Berton, Rafael ^[2] ; Soares, Sandro Gomes ^[3] ; Pessotti, Dayelle S. ^[2] ; Camacho, Mauricio F. ^[2] ; Andrade-Silva, Debora ^[4] ; Barcick, Uilla ^[2] ; Serrano, Solange M. T. ^[4] ; Chammas, Roger ^[5] ; Nascimento, Maria C. V. ^[1] ; Zelanis, Andre ^[2]

Affiliation

^[1] Fed Univ Sao Paulo ICT UNIFESP, Dept Sci & Technol, Sao Jose Dos Campos, SP - Brazil

^[2] Fed Univ Sao Paulo ICT UNIFESP, Dept Sci & Technol, Funct Prote Lab, Sao Jose Dos Campos, SP - Brazil

^[3] Univ Cambridge, Dept Biochem, Cambridge - England

^[4] Inst Butantan, Ctr Toxins Immune Response & Cell Signaling CeTIC, Lab Toxinol Aplicada, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF PROTEOMICS; v. 232, FEB 10 2021.
• Web of Science Citations: 0

Abstract

Protein-protein interaction networks (PPINs) are static representations of protein connections in which topological features such as subgraphs (communities) may contain proteins functionally related, revealing an additional layer of interactome complexity. We created two PPINs from the secretomes of a paired set of murine melanocytes (a normal melanocyte and its transformed phenotype). Community structures, identified by a graph clustering algorithm, resulted in the identification of subgraphs in both networks. Interestingly, the underlying structure of such communities revealed shared and exclusive proteins (core and exclusive nodes, respectively), in addition to proteins that changed their location within each community (rewired nodes). Functional enrichment analysis of core nodes revealed conserved biological functions in both networks whereas exclusive and rewired nodes in the tumoral phenotype network were enriched in cancer-related processes, including TGF beta signaling. We found a remarkable shift in the tumoral interactome, resulting in an emerging pattern which was driven by the presence of exclusive nodes and may represent functional network motifs. Our findings suggest that the rearrangement in the tumoral interactome may be correlated with the malignant transformation of melanocytes associated with substrate adhesion impediment. The interactions found in core and new/rewired nodes might potentially be targeted for therapeutic intervention in melanoma treatment. Significance: Malignant transformation is a result of synergistic action of multiple molecular factors in which genetic alterations as well as protein expression play paramount roles. During oncogenesis, cellular crosstalk through the secretion of soluble mediators modulates the phenotype of transformed cells which ultimately enables them to successfully disrupt important signaling pathways, including those related to cell growth and proliferation. Therefore, in this work we profiled the secretomes of a paired set of normal and transformed phenotypes of a murine melanocyte. After assembling the two interactomes, clusters of functionally related proteins (network communities) were observed as well as emerging patterns of network rewiring which may represent an interactome signature of transformed cells. In summary, the significance of this study relies on the understanding of the repertoire of `normal' and `tumoral' secretomes and, more importantly, the set of interacting proteins (the interactome) in both of these conditions, which may reveal key components that might be potentially targeted for therapeutic intervention. (AU)

• FAPESP's process: 17/22330-3 - Investigation of cell surface proteome of murine melanocytes treated with tumor secretome
• Grantee: Rafael Berton Correia Ramos
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 15/21660-4 - Hibridizing heuristic and exact methods to approach combinatorial optimization problems
• Grantee: Mariá Cristina Vasconcelos Nascimento Rosset
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07375-0 - CeMEAI - Center for Mathematical Sciences Applied to Industry
• Grantee: Francisco Louzada Neto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/24185-0 - Spectral analysis to anomaly detection in dynamic attributed graphs
• Grantee: Rodrigo Francisquini da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/06579-3 - System-wide analysis of N-terminal processing and protein diversity in the secretome of tumor cells
• Grantee: André Zelanis Palitot Pereira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 19/10817-0 - Evaluation of the proteolytic processing of TGFB citokyne in melanoma secretomes
• Grantee: Uilla Barcick
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC