Integrative multi-omics and drug-response characterization of patient-derived prostate cancer primary cells

Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Herein,we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients,including gene mutations,mRNA/protein/surface protein distributions,and pharmaceutical responses.The multi-omics analyses identify Anterior Gradient 2(AGR2)as a pre-operative prognostic biomarker in PCa.Through the drug library screening,we describe crizotinib as a selective compound for malignant PCa primary cells.We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations.Surprisingly,the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model.Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses,allowing for more precise diagnosis and therapies.

A novel in vitro prognostic model of bladder cancer based on urine-derived living tumor cells

Bladder cancer(BLCA)remains a difficult malignancy to manage because of its high recurrence,intense follow-up,and invasive diagnostic and treatment techniques.Immune checkpoint inhibitors(ICIs)have forged a new direction for the treatment of BLCA,but it is currently challenging to predict whether an individual patient will be sensitive to ICIs.We collected 43 urine/tumor samples from BLCA patients for primary bladder cancer cells(BCCs)culturing using our previously reported BCC culture platform.We used flow cytometry(FCM)to measure the expression levels of Programmed Death-Ligand 1(PD-L1)on BCCs before and after interferon-gamma(IFN-γ)treatment and found that PD-L1 expression and the sensitivities to IFN-γvaried among patients.RNA-sequencing,western blotting,and programmed death-1(PD-1)binding assays confirmed that the BCC FCM-based PD-L1 detection platform(BC-PD-L1)was reliable and was not hindered by the glycosylation of PD-L1.In the subsequent retrospective study,we found that IFN-γ-stimulated PD-L1(sPD-L1)expression on BCCs detected by BC-PD-L1 could predict the prognosis of BLCA patients.Importantly,the prognostic value was similar or even better in urine-derived BC-PD-L1(UBC-PD-L1).Transcriptome analysis showed that BCCs with high sPD-L1 tended to enrich genes associated with the collagen-containing extracellular matrix,cell–cell adhesion,and positive regulation of the immune system.In addition,the UBC-PD-L1 also exhibited predictive value for ICI response in BLCA patients.In conclusion,as a novel personalized urine-detection method,UBC-PD-L1 may provide a rapid,accurate,and non-invasive tool for monitoring tumor progression,predicting therapeutic responses,and helping improve BLCA clinical treatment in future.