title: Elimination of epithelial-like and mesenchymal-like breast cancer stem cells to inhibit metastasis following nanoparticle-mediated photothermal therapy.
abstract: Increasing evidence suggesting breast cancer stem cells (BCSCs) drive metastasis and evade traditional therapies underscores a critical need to exploit the untapped potential of nanotechnology to develop innovative therapies that will significantly improve patient survival. Photothermal therapy (PTT) to induce localized hyperthermia is one of few nanoparticle-based treatments to enter clinical trials in human cancer patients, and has recently gained attention for its ability to induce a systemic immune response targeting distal cancer cells in mouse models. Here, we first conduct classic cancer stem cell (CSC) assays, both in vitro and in immune-compromised mice, to demonstrate that PTT mediated by highly crystallized iron oxide nanoparticles effectively eliminates BCSCs in translational models of triple negative breast cancer. PTT in vitro preferentially targets epithelial-like ALDH + BCSCs, followed by mesenchymal-like CD44+/CD24- BCSCs, compared to bulk cancer cells. PTT inhibits BCSC self-renewal through reduction of mammosphere formation in primary and secondary generations. Secondary implantation in NOD/SCID mice reveals the ability of PTT to impede BCSC-driven tumor formation. Next, we explore the translational potential of PTT using metastatic and immune-competent mouse models. PTT to inhibit BCSCs significantly reduces metastasis to the lung and lymph nodes. In immune-competent BALB/c mice, PTT effectively eliminates ALDH + BCSCs. These results suggest the feasibility of incorporating PTT into standard clinical treatments such as surgery to enhance BCSC destruction and inhibit metastasis, and the potential of such combination therapy to improve long-term survival in patients with metastatic breast cancer.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Hayley J
authors.initials: HJ
authors.lastname: Paholak
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Stevers
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, MI, United States. Electronic address: hongweic@med.umich.edu.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Chen
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Burnett
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States; Georgia Regents University Cancer Center, Augusta, GA, United States.
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Sean P
authors.initials: SP
authors.lastname: McDermott
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Yadwinder
authors.initials: Y
authors.lastname: Deol
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Clouthier
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Tahra
authors.initials: T
authors.lastname: Luther
authors.affiliation: Departments of Surgery and Pathology, University of Michigan Medical Center, Ann Arbor, MI, United States.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, United States.
authors.forename: Max S
authors.initials: MS
authors.lastname: Wicha
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor, MI, United States. Electronic address: duxins@med.umich.edu.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects*; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D007259:Infrared Rays; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage* / Q000528:radiation effects; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000528:radiation effects*; D010789:Phototherapy / Q000379:methods*; D016896:Treatment Outcome
keywords: Breast cancer stem cells; Iron oxide nanoparticles; Metastasis inhibition; Photothermal therapy; Triple negative breast cancer