title: Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1.
abstract: Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Chi Lam
authors.initials: CL
authors.lastname: Au Yeung
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Ngai-Na
authors.initials: NN
authors.lastname: Co
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Tsuruga
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Tsz-Lun
authors.initials: TL
authors.lastname: Yeung
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Suet-Ying
authors.initials: SY
authors.lastname: Kwan
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Leung
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Lu
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Kenny
authors.initials: K
authors.lastname: Kwan
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Kwong-Kwok
authors.identifier: http://orcid.org/0000-0002-0375-6669
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1362, Houston, Texas 77030, USA.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D053477:Apoptotic Protease-Activating Factor 1; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D017239:Paclitaxel