Proteomic Profiling of Extracellular Vesicles Distinguishes Prostate Cancer Molecular Subtypes

Area of Science:

• Oncology
• Proteomics
• Biomarker Discovery

Background:

• Prostate cancer is a common malignancy in men, often driven by androgen receptor (AR) signaling.
• Aggressive subtypes emerge, characterized by loss of AR and gain of neuroendocrine (NE) features (AR-/NE+) or loss of both (AR-/NE-).
• Extracellular vesicles (EVs) are promising for non-invasive liquid biopsies due to their cargo of origin-specific biomolecules.

Purpose of the Study:

• To characterize the proteome of EVs from various prostate cancer subtypes.
• To identify EV protein signatures correlating with distinct tumor molecular profiles (AR+, AR-/NE+, AR-/NE-).
• To assess the utility of EV proteomics for prognostication and clinical decision-making, especially for aggressive subtypes.

Main Methods:

• Shotgun proteomics and mass spectrometry were employed to analyze EV protein content.
• EVs were isolated from established prostate cancer cell lines representing AR+, AR-/NE+, and AR-/NE- subtypes.
• Proteomic data were integrated with patient-derived EV data for validation.

Main Results:

• A total of 3952 EV proteins were identified, with profiles clustering by tumor subtype.
• EVs from AR+ cells showed proteins regulated by AR and mTOR signaling.
• EVs from AR-/NE+ and AR-/NE- subtypes displayed characteristic NE markers and basal/EMT-related proteins, respectively.
• Integration with patient data revealed 2733 overlapping proteins, including subtype-specific markers and AR activity indicators.

Conclusions:

• EV proteomic profiling effectively distinguishes prostate cancer subtypes, including aggressive AR-/NE+ and AR-/NE- forms.
• EVs contain molecular signatures relevant for prognostication and can serve as biomarkers for liquid biopsy.
• This proteomic approach holds potential for optimizing clinical decision-making, particularly for rare and aggressive prostate cancer subtypes.