SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells

C. Canino, F. Mori, A. Cambria, A. Diamantini, S. Germoni, G. Alessandrini, G. Borsellino, R. Z. Galati, L. Battistini, R. Blandino, F. Facciolo, G. Citro, S. Strano, P. Muti, G. Blandino, M. Cioce

Research output: Contribution to journalArticle

Abstract

Here we show that pemetrexed-treated mesothelioma cells undergo accelerated senescence. This is characterized by the secretion of proinflammatory and mitogenic cytokines, reminiscent of an SASP (senescence-associated secretory phenotype). Conditioned media from senescent MPM (malignant pleural mesothelioma) cells trigger the emergence of EMT (epithelial-to-mesenchymal)- like, clonogenic and chemoresistant cell subpopulations, expressing high levels of ALDH (aldehyde dehydrogenase) activity (ALDH bright cells). We show by fluorescence-activated cell sorting of purified ALDH bright and ALDH low cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDH bright cells exist within primary MPM specimens and enrichment for ALDH bright cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RAS v12 expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RAS v12 expression. We identify STAT3 activation as a crucial event downstream to SASP signaling. In fact, small hairpin RNA-mediated ablation of STAT3 deeply attenuates the induction of EMT genes and the increase of ALDH bright cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.

Original languageEnglish
Pages (from-to)3148-3163
Number of pages16
JournalOncogene
Volume31
Issue number26
DOIs
Publication statusPublished - Jun 28 2012

Keywords

  • chemoresistance
  • EMT
  • mesothelioma
  • SASP

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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  • Cite this

    Canino, C., Mori, F., Cambria, A., Diamantini, A., Germoni, S., Alessandrini, G., Borsellino, G., Galati, R. Z., Battistini, L., Blandino, R., Facciolo, F., Citro, G., Strano, S., Muti, P., Blandino, G., & Cioce, M. (2012). SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene, 31(26), 3148-3163. https://doi.org/10.1038/onc.2011.485