title: Targeting exosomes from preadipocytes inhibits preadipocyte to cancer stem cell signaling in early-stage breast cancer.
abstract: The tumor microenvironment plays a critical role in regulating breast tumor progression. Signaling between preadipocytes and breast cancer cells has been found to promote breast tumor formation and metastasis. Exosomes secreted from preadipocytes are important components of the cancer stem cell niche. Mouse preadipocytes (3T3L1) are treated with the natural antitumor compound shikonin (SK) and exosomes derived from mouse preadipocytes are co-cultured with MCF10DCIS cells. We examine how preadipocyte-derived exosomes can regulate early-stage breast cancer via regulating stem cell renewal, cell migration, and tumor formation. We identify a critical miR-140/SOX2/SOX9 axis that regulates differentiation, stemness, and migration in the tumor microenvironment. Next, we find that the natural antitumor compound SK can inhibit preadipocyte signaling inhibiting nearby ductal carcinoma in situ (DCIS) cells. Through co-culture experiments, we find that SK-treated preadipocytes secrete exosomes with high levels of miR-140, which can impact nearby DCIS cells through targeting SOX9 signaling. Finally, we find that preadipocyte-derived exosomes promote tumorigenesis in vivo, providing strong support for the importance of exosomal signaling in the tumor microenvironment. Our data also show that targeting the tumor microenvironment may assist in blocking tumor progression.
authors.affiliation: Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
authors.forename: Ramkishore
authors.initials: R
authors.lastname: Gernapudi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Yongshu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolfson
authors.forename: Sanchita
authors.initials: S
authors.lastname: Roy
authors.forename: Nadire
authors.initials: N
authors.lastname: Duru
authors.forename: Gabriel
authors.initials: G
authors.lastname: Eades
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D055354:Exosomes / Q000235:genetics / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009285:Naphthoquinones / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055758:SOX9 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; C544302:Mirn140 microRNA, human; D009285:Naphthoquinones; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C016101:shikonin