Abstract
Prostate cancer is initially treated via androgen deprivation therapy (ADT), a highly successful treatment in the initial pursuit of tumour regression, but commonly restricted by the eventual emergence of a more lethal ‘castrate resistant’ (CRPC) form of the disease. Intracrine pathways that utilize dehydroepiandrosterone (DHEA) or other circulatory precursor steroids are thought to generate relevant levels of growth-stimulating androgens such as testosterone (T) and dihydrotestosterone (DHT). Decoding this tissue-specific metabolic pathway is key for the development of novel therapeutic treatments. Mass spectrometry imaging (MSI) is an analytical technique that allows the visualization of the distribution of numerous classes of biomolecules within tissue sections. The analysis of androgens by liquid chromatography mass spectrometry (LC/MS)-based methods however presents a challenge due to their generally poor ionization efficiency and low physiological endogenous levels. In MSI, on-tissue chemical derivatization (OTCD) has enabled the limits of steroids to be imaged within tissues to be pushed by overcoming poor ionization performance. However, isobaric interference of key androgen derivatives such as T and DHEA can severely hamper studying the intracrinology in several diseases. Here, we have evaluated the use of laser induced post-ionization (MALDI-2) combined with trapped ion mobility separation (TIMS) and orthogonal time-of-flight (QTOF) MS for the visualization of isobaric derivatized androgens in murine tumour xenograft at about 50 μm spatial resolution. With this combination, isobaric T and DHEA were separated in tissue sections and the signals of derivatized steroids enhanced by about 20 times. The combination of TIMS and MALDI-2 thus shows unique potential to study tissue intracrinology within target tissues. This could offer the opportunity for many novel insights into tissue-specific androgen biology.
Highlights
Advanced localized prostate cancer (PCa) is commonly treated by androgen deprivation therapy (ADT).[1]
The retention of androgen signalling has been suggested upon this mechanism of intracrine conversion, with numerous studies showing the presence of a different androgen metabolism pathway as shown in Fig. 1.1,5 unravelling this tissue-speci c metabolic pathway is key for the development of novel therapeutic treatments
Off-tissue derivatization screening and trapped ion mobility separation (TIMS) separation. This novel application of on-tissue chemical derivatization (OTCD) coupled with MALDI-2 and TIMS enhanced on-tissue detection by laser induced postionization on readily charged androgen derivatives and allowed separation of endogenous isobaric androgen derivatives, which yielded intense signal and distinct gas-phase conformations upon TIMS analysis
Summary
Such as testosterone (T) and to block tumour cell growth. Castrate resistant prostate cancer (CRPC) is a more lethal and difficult form of PCa to treat and it is currently under debate on how this alternative form has originated.[1,2,3] Steroid intracrinology was rst acknowledged by Labrie et al.,[4] in which castrated rats obtained the ability to maintain levels of T and dihydrotestosterone (DHT). Mass spectrometry imaging (MSI) is a versatile and multiplex analytical method, allowing the production of a 2D ion image of multiple metabolites in biological tissues.[6] Androgens have been demonstrated to show poor ionization efficiency in liquid To overcome these issues, we here assessed, for the rst time, the use of laser-induced post-ionization (MALDI-2), combined with trapped ion mobility separation (TIMS) (MALDI-2-TIMS) in the identi cation and distribution analysis of isobaric derivatized androgen in a murine tumour xenogra model. The spatial distribution of both DHEA and T in a murine xenogra model was achieved
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