Unravelling Prostate Cancer Heterogeneity Using Spatial Approaches to Lipidomics and Transcriptomics

SIMPLE SUMMARY: Prostate cancer is a heterogenous disease in terms of disease aggressiveness and therapy response, leading to dilemmas in treatment decisions. This heterogeneity reflects the multifocal nature of prostate cancer and its diversity in cellular and molecular composition, necessitating spatial molecular approaches. Here in view of the emerging importance of rewired lipid metabolism as a source of biomarkers and therapeutic targets for prostate cancer, we highlight recent advancements in technologies that enable the spatial mapping of lipids and related metabolic pathways associated with prostate cancer development and progression. We also evaluate their potential for future implementation in treatment decision-making in the clinical management of prostate cancer. ABSTRACT: Due to advances in the detection and management of prostate cancer over the past 20 years, most cases of localised disease are now potentially curable by surgery or radiotherapy, or amenable to active surveillance without treatment. However, this has given rise to a new dilemma for disease management; the inability to distinguish indolent from lethal, aggressive forms of prostate cancer, leading to substantial overtreatment of some patients and delayed intervention for others. Driving this uncertainty is the critical deficit of novel targets for systemic therapy and of validated biomarkers that can inform treatment decision-making and to select and monitor therapy. In part, this lack of progress reflects the inherent challenge of undertaking target and biomarker discovery in clinical prostate tumours, which are cellularly heterogeneous and multifocal, necessitating the use of spatial analytical approaches. In this review, the principles of mass spectrometry-based lipid imaging and complementary gene-based spatial omics technologies, their application to prostate cancer and recent advancements in these technologies are considered. We put in perspective studies that describe spatially-resolved lipid maps and metabolic genes that are associated with prostate tumours compared to benign tissue and increased risk of disease progression, with the aim of evaluating the future implementation of spatial lipidomics and complementary transcriptomics for prognostication, target identification and treatment decision-making for prostate cancer.