TY - JOUR T1 - The distinct role of ALDH1A1 and ALDH1A3 in the regulation of prostate cancer metastases JF - bioRxiv DO - 10.1101/2021.05.08.443223 SP - 2021.05.08.443223 AU - Ielizaveta Gorodetska AU - Anne Offermann AU - Jakob Püschel AU - Vasyl Lukiyanchuk AU - Diana Gaete AU - Anastasia Kurzyukova AU - Vera Labitzky AU - Franziska Schwarz AU - Tobias Lange AU - Franziska Knopf AU - Ben Wielockx AU - Mechthild Krause AU - Sven Perner AU - Anna Dubrovska Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/10/2021.05.08.443223.abstract N2 - Cancer stem cells (CSC) are characterized by high self-renewal capacity, tumor-initiating potential, and therapy resistance. Aldehyde dehydrogenase (ALDH)+ cell population serves as an indicator of prostate CSCs with increased therapy resistance, enhanced DNA double-strand break repair, and activated epithelial-mesenchymal transition (EMT) and migration. Numerous ALDH genes contribute to ALDH enzymatic activity; however, only some of them showed clinical relevance. We found that ALDH1A1 and ALDH1A3 genes functionally regulate CSC properties and radiation sensitivity of PCa. We revealed a negative correlation between ALDH1A1 and ALDH1A3 expression in publicly available prostate cancer (PCa) datasets and demonstrated that ALDH1A1 and ALDH1A3 have opposing predictive value for biochemical recurrence-free survival. Our data suggest an association of ALDH1A1 with the metastatic burden, elucidating the role of ALDH genes in the metastatic spread and homing to the bone, which can be, at least partially, attributed to regulating the transforming growth factor beta 1 (TGFB1) and matrix metalloproteinases (MMPs). ALDH genes play a diverse role in PCa development under AR and β-catenin-dependent regulation, with ALDH1A1 becoming dominant in later stages of tumor development when PCa cells gain androgen independence. Taken together, our results indicate that ALDH1A1 and ALDH1A3 modulate PCa radiosensitivity, regulate CSCs phenotype, and spread of PCa cells to the bone, therefore having clinical implication for identifying patients at high risk for progression to metastatic disease.Competing Interest StatementThe authors have declared no competing interest.ALDHaldehyde dehydrogenaseARandrogen receptorBAAAbodipy-aminoacetaldehydeBAAbodipy-aminoacetateBMbone metastaticCSCcancer stem cellDEABdiethylaminobenzaldehydeDHTdihydrotestosteroneDMEMDulbecco’s Modified Eagles MediumDMSOdimethyl sulfoxideDoCduct of Cuvierdpfdays post fertilizationDTTdithiothreitolECMextracellular matrixEGFepidermal growth factorEMTepithelial-mesenchymal transitionEnzaEnzalutamideFBSfetal bovine serumFFPEfresh frozen paraffin embeddedFGFfibroblast growth factorFITCfluorescein isothiocyanateFSCforward scattergDNAgenomic DNAi.c.intracardiacIHCimmunohistochemistryiPSAinitial prostate-specific antigen levelsLNlymph nodeLMlung metastaticLucluciferasemCRPCmetastatic castration resistant prostate cancerMMPmatrix metalloproteaseNSGNOD scid gamma mousePparentalPBSphosphate-buffered salinePCaprostate cancerPEplating efficacyPFAparaformaldehydePIpropidium iodidePTprimary tumorRPMIRoswell Park Memorial Institute MediumRRradioresistantRTroom temperatureRTradiation therapy-RTsample without added reverse transcriptase enzymeSFsurviving fractionshNAnon-silencing small hairpin RNAshRNAsmall hairpin RNAsiRNAsmall interfering RNAsiSCRscrambled small interfering RNASPSSStatistical Package for the Social SciencesSSCside scatterSUMOStatistical Utility for Microarray and Omics data softwareTCGAThe Cancer Genome AtlasTMAtissue microarrayTNMtumor, nodus и metastasisWFwide fieldZolzoledronic acid ER -