Pyrvinium pamoate induces death of triple-negative breast cancer stem-like cells and reduces metastases through effects on lipid anabolism

Ruggero De Maria Marchiano, Rosanna Dattilo, Carla Mottini, Emanuela Camera, Alessia Lamolinara, Noam Auslander, Ginevra Doglioni, Michela Muscolini, Wei Tang, Melanie Planque, Cristiana Ercolani, Simonetta Buglioni, Isabella Manni, Daniela Trisciuoglio, Alessandra Boe, Sveva Grande, Anna Maria Luciani, Manuela Iezzi, Gennaro Ciliberto, Stefan AmbsSarah-Maria Fendt, Eytan Ruppin, Luca Cardone

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Cancer stem-like cells (CSC) induce aggressive tumor phenotypes such as metastasis formation, which is associated with poor prognosis in triple-negative breast cancer (TNBC). Repurposing of FDA-approved drugs that can eradicate the CSC subcompartment in primary tumors may prevent metastatic disease, thus representing an effective strategy to improve the prognosis of TNBC. Here, we investigated spheroid-forming cells in a metastatic TNBC model. This strategy enabled us to specifically study a population of long-lived tumor cells enriched in CSCs, which show stem-like characteristics and induce metastases. To repurpose FDA-approved drugs potentially toxic for CSCs, we focused on pyrvinium pamoate (PP), an anthelmintic drug with documented anticancer activity in preclinical models. PP induced cytotoxic effects in CSCs and prevented metastasis formation. Mechanistically, the cell killing effects of PP were a result of inhibition of lipid anabolism and, more specifically, the impairment of anabolic flux from glucose to cholesterol and fatty acids. CSCs were strongly dependent upon activation of lipid biosynthetic pathways; activation of these pathways exhibited an unfavorable prognostic value in a cohort of breast cancer patients, where it predicted high probability of metastatic dissemination and tumor relapse. Overall, this work describes a new approach to target aggressive CSCs that may substantially improve clinical outcomes for patients with TNBC, who currently lack effective targeted therapeutic options.
Lingua originaleEnglish
pagine (da-a)4087-4102
Numero di pagine16
RivistaCancer Research
Volume80
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

  • Animals
  • Antineoplastic Agents
  • Apoptosis
  • Cell Line, Tumor
  • Cell Movement
  • Cholesterol
  • Drug Repositioning
  • Female
  • Glucose
  • Humans
  • Lipid Metabolism
  • Mice, Inbred NOD
  • Neoplastic Stem Cells
  • Pyrvinium Compounds
  • Triple Negative Breast Neoplasms
  • Xenograft Model Antitumor Assays

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