Origins and clinical relevance of proteoforms in pediatric malignancies

Abstract

Introduction: Cancer changes the proteome in complex ways that reach well beyond simple changes in protein abundance. Genomic and transcriptional variations and post-translational protein modification create functional variants of a protein, known as proteoforms. Childhood cancers have fewer genomic alterations but show equally dramatic phenotypic changes as malignant cells in adults. Therefore, unraveling the complexities of the proteome is even more important in pediatric malignancies. Areas covered: In this review, the biological origins of proteoforms and technological advancements in the study of proteoforms are discussed. Particular emphasis is given to their implication in childhood malignancies and the critical role of cancer-specific proteoforms for the next generation of cancer therapies and diagnostics. Expert opinion: Recent advancements in technology have led to a better understanding of the underlying mechanisms of tumorigenesis. This has been critical for the development of more effective and less harmful treatments that are based on direct targeting of altered proteins and deregulated pathways. As proteome coverage and the ability to detect complex proteoforms increase, the most need for change is in data compilation and database availability to mediate high-level data analysis and allow for better functional annotation of proteoforms.

PDX models reflect the proteome landscape of pediatric acute lymphoblastic leukemia but divert in select pathways

“…Following translation, proteins can be diversely modified, and made capable to simultaneously regulate multiple processes and pathways in separate cellular locations 12 . Formation of functionally different proteoforms 13 by post-translational modification (PTM) is frequently in diseases, including childhood cancers 14 . Protein phosphorylation and irreversible proteolytic processing are among the main PTMs that regulate cellular processes and contribute to the development and progression of cancer.…”

A Two-Dimensional Affinity Capture and Separation Mini-Platform for the Isolation, Enrichment, and Quantification of Biomarkers and Its Potential Use for Liquid Biopsy

“…This term captures the disparate sources of biological variation that alter primary sequence and composition at the whole-protein level [ 138 , 139 , 140 ]. The process of identifying aberrantly expressed proteins and disease-associated proteoforms has led to a better understanding of the underlying mechanisms of diseases, particularly tumorigenesis [ 141 ]. Figure 3 D shows an electropherogram of immunoreactive A1 beta casein-derived casormorphin-5 and casomorphin-7 extracted from urine and analyzed by IACE.…”

Implementation of MALDI Mass Spectrometry Imaging in Cancer Proteomics Research: Applications and Challenges

“…Studying proteins in the context of cancer is of major relevance to understand the underlying biology at the molecular level; implementing proteomic approaches in cancer research can provide new crucial insights into tumor biology by analyzing protein expression levels and modifications resulting in different functioning. Moreover, proteomics can reveal new pathways involved in cancer progression and may lead to new therapeutic approaches [ 4 ].…”

“…Using mass spectrometry, not only the protein content in different types of samples such as blood, serum, urine and tissues can be identified, but even the different proteoforms within each sample can be detected with top-down proteomics. In addition, mass spectrometry is a (semi-)quantitative technique, which allows comparison of protein abundances between different conditions [ 4 , 5 ]. Furthermore, protein interactions can be studied using mass spectrometric approaches and even PTMs can be identified and mapped [ 3 ].…”