Cell-surface proteomics for the identification of novel therapeutic targets in cancer

Abstract

Cancer is the second most common cause of death worldwide and its heterogeneity complicates therapy. Standard cytotoxic regiments disrupt rapidly dividing cells, regardless of their neoplastic status. The introduction of less toxic targeted therapies has partially contributed to the observed decrease in cancer-related mortality. Cell-surface proteins represent attractive targets for therapy, due to their easily-accessible localization and their involvement in essential signaling pathways, often dysregulated in cancer. Despite their clinical appeal, cell-surface proteins are often underrepresented in standard proteomic data sets, due to their poor solubility and lower expression levels compared to intracellular proteins. Areas covered: This review will summarize some of the available techniques for enriching the cell-surface proteome, and discuss their advantages, limitations and applicability to clinical sample-testing. Moreover, we discuss currently available strategies for the development of novel targeted therapies in cancer. Expert commentary: The interest in elucidating the cancer-associated surfaceome is growing and will likely benefit from recent advancements in instrument sensitivity, method development, and a growing body of high-quality proteomics databases. Multiomics studies, in combination with functional validations (e.g. dropout screens), and evaluation of the healthy surfaceome, will likely aid in the selection of relevant targets for future therapy development.

Finding the Keys to the CAR: Identifying Novel Target Antigens for T Cell Redirection Immunotherapies

“…Cell surface proteomics is a collection of techniques which directly and selectively identifies the surface proteome. The analysis of the proteome relies on enrichment and capture or solubilisation of cell surface proteins before identification by MS. To do this there are a variety of methods available, such as ultracentrifugation, aminooxybiotinylation or silica bead coating [42]. These techniques each employ a different property of either the cell surface proteins themselves or that of the lipid membrane.…”

“…However, due to the nature of MS, each of these approaches are biased towards the identification of the most abundant proteins, or those most conducive to purification, within a sample. Standard total proteomic approaches also often under-represent the surface proteome due to their lower expression and detection compared to intracellular proteins (recently reviewed in [42]). Constant advances in technology improve screening methodologies, and proteomics is a rapidly expanding discipline.…”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…Checkpoint immunotherapy shows that the most efficient way to destroy a cancer system is by acting directly on binary contacts between ligands and their receptors exposed on the surface of APCs, cancer, and stromal immune cells. Cell‐surface proteins represent attractive targets for therapy, due to their accessibility and involvement in essential signaling pathways, which are often dysregulated in cancer . A receptor‐ligand interaction is in itself a single key event—the binding of a signaling molecule (ligand), to its receiving molecule (receptor).…”

“…Cell-surface proteins represent attractive targets for therapy, due to their accessibility and involvement in essential signaling pathways, which are often dysregulated in cancer. [61] A receptor-ligand interaction is in itself a single key event-the binding of a signaling molecule (ligand), to its receiving molecule (receptor). This binding (interaction) is relatively simple, and can be described by simple kinetic equations.…”

Data mining in mass spectrometry-based proteomics studies

“…Thus, the identification and quantification of differences between two or more physiological states of a biological system can be defined as changes on the control sample, determining the up-or down-regulation of such protein 1 . These approaches have been extensively applied in biomedical research for the understanding of diseases, including protein-based biomarker discovery for early detection and monitoring of different types of cancer 2 , the analysis of abnormal protein phosphorylation patterns associated with diseases 3 and the identification of therapeutic targets 4 .…”