: Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem-like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors.

Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells / Ascenzi, Francesca; Esposito, Antonella; Bruschini, Sara; Salvati, Valentina; De Vitis, Claudia; De Arcangelis, Valeria; Ricci, Giulia; Catizione, Angiolina; di Martino, Simona; Buglioni, Simonetta; Bassi, Massimiliano; Venuta, Federico; De Nicola, Francesca; Massacci, Alice; Grassucci, Isabella; Pallocca, Matteo; Ricci, Alberto; Fanciulli, Maurizio; Ciliberto, Gennaro; Mancini, Rita. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 15:4(2024), pp. 1-13. [10.1038/s41419-024-06667-w]

Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells

Bruschini, Sara;Salvati, Valentina;De Vitis, Claudia;De Arcangelis, Valeria;Bassi, Massimiliano;Venuta, Federico;Pallocca, Matteo;Ricci, Alberto;Fanciulli, Maurizio;Mancini, Rita
2024

Abstract

: Scientific literature supports the evidence that cancer stem cells (CSCs) retain inside low reactive oxygen species (ROS) levels and are, therefore, less susceptible to cell death, including ferroptosis, a type of cell death dependent on iron-driven lipid peroxidation. A collection of lung adenocarcinoma (LUAD) primary cell lines derived from malignant pleural effusions (MPEs) of patients was used to obtain 3D spheroids enriched for stem-like properties. We observed that the ferroptosis inducer RSL3 triggered lipid peroxidation and cell death in LUAD cells when grown in 2D conditions; however, when grown in 3D conditions, all cell lines underwent a phenotypic switch, exhibiting substantial resistance to RSL3 and, therefore, protection against ferroptotic cell death. Interestingly, this phenomenon was reversed by disrupting 3D cells and growing them back in adherence, supporting the idea of CSCs plasticity, which holds that cancer cells have the dynamic ability to transition between a CSC state and a non-CSC state. Molecular analyses showed that ferroptosis resistance in 3D spheroids correlated with an increased expression of antioxidant genes and high levels of proteins involved in iron storage and export, indicating protection against oxidative stress and low availability of iron for the initiation of ferroptosis. Moreover, transcriptomic analyses highlighted a novel subset of genes commonly modulated in 3D spheroids and potentially capable of driving ferroptosis protection in LUAD-CSCs, thus allowing to better understand the mechanisms of CSC-mediated drug resistance in tumors.
2024
cancer stem cell, ferroptosis, lung cancer
01 Pubblicazione su rivista::01a Articolo in rivista
Identification of a set of genes potentially responsible for resistance to ferroptosis in lung adenocarcinoma cancer stem cells / Ascenzi, Francesca; Esposito, Antonella; Bruschini, Sara; Salvati, Valentina; De Vitis, Claudia; De Arcangelis, Valeria; Ricci, Giulia; Catizione, Angiolina; di Martino, Simona; Buglioni, Simonetta; Bassi, Massimiliano; Venuta, Federico; De Nicola, Francesca; Massacci, Alice; Grassucci, Isabella; Pallocca, Matteo; Ricci, Alberto; Fanciulli, Maurizio; Ciliberto, Gennaro; Mancini, Rita. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 15:4(2024), pp. 1-13. [10.1038/s41419-024-06667-w]
File allegati a questo prodotto
File Dimensione Formato  
Ascenzi_Identification_2024.pdf

accesso aperto

Note: articolo in rivista
Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 4.61 MB
Formato Adobe PDF
4.61 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1709529
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact