Proteomic Analysis of the Unfolded Protein Response in Melanoma

Abstract

Despite enormous advancements made in the last decade in the treatment of metastatic melanoma, due to drug resistance and drug toxicities, new therapies and treatment strategies are needed. Additionally, there are no prognostic biomarkers for metastatic disease able to predict outcome. Thirty-two potential biomarkers were analysed by selected reaction monitoring (SRM) in 30 stage III melanoma patients. A 14-protein panel was discovered, able to predict patients likely to have poor outcome and therefore potentially benefit from aggressive therapeutic strategies.

From the above study, the Unfolded Protein Response (UPR) was revealed to be a major cellular pathway up-regulated in patients with poor outcome. The UPR is a cellular stress response, which is initiated by a build-up of unfolded protein in the endoplasmic reticulum (ER). Increased activation of the UPR is associated with several cancers however, the mechanisms used to promote tumour progression and metastases are not well understood.

To characterise this stress response, the UPR was activated in melanoma cell line models. Using quantitative mass spectrometry 64 proteins were identified as differentially abundant with increased UPR activation. Among them, eight UPR-associated proteins were validated by SRM, identifying these proteins as core modulators of the UPR. An in silico analysis of the eight UPR-associated proteins in pan-cancer patient data across 16 solid tumour types revealed the eight UPR-associated proteins were markers of poor survival across cancer types. The combined data demonstrates the UPR is a major contributor to cancer progression.

The study contributes to our knowledge of melanoma biology by elucidating the broad impact of the UPR on several cellular pathways and mechanisms that would promote tumour growth and increase the metastatic potential of melanoma. Furthermore, novel UPR drug targets were identified, including cooperative pathways that could be targeted in combinatorial therapies