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

Oncogene volume 31, pages 3148–3163 (2012)Cite this article

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 (ALDHbright cells). We show by fluorescence-activated cell sorting of purified ALDHbright and ALDHlow cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDHbright cells exist within primary MPM specimens and enrichment for ALDHbright cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RASv12 expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RASv12 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 ALDHbright cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.

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Abbreviations

EMT:

epithelial-to-mesenchymal–transition

MPE:

mesothelial peritoneal exudate

SASP:

senescence-associated-secretory-phenotype

TICs:

tumor-initiating–cells

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Acknowledgements

We thank Ms Tania Merlino (Regina Elena Cancer Institute, Rome) for revising and proofreading the manuscript and Dr Frank Sinicrope (Rochester, MN) for the ShSTAT3 vectors available at ADDGENE (UK). We acknowledge INAIL (Italian Workers’ Compensation Authority) for grant support to GB.

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Authors and Affiliations

  1. Translational Oncogenomic Unit, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

    C Canino, G Blandino & M Cioce

  2. Molecular Chemoprevention Group, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

    F Mori, R Galati & S Strano

  3. S Vincenzo Hospital, Taormina, Italy

    A Cambria & R Blandino

  4. Neuroimmunology Unit IRCCS Santa Lucia Foundation, Rome, Italy

    A Diamantini, G Borsellino & L Battistini

  5. SAFU Department, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

    S Germoni & G Citro

  6. Unit of Thoracic Surgery, Italian National Cancer Institute, Rome, Italy

    G Alessandrini & F Facciolo

  7. Scientific Director's Office, Italian National Cancer Institute ‘Regina Elena’, Rome, Italy

    P Muti

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  1. C Canino
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Correspondence to G Blandino or M Cioce.

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Canino, C., Mori, F., Cambria, A. et al. SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells. Oncogene 31, 3148–3163 (2012). https://doi.org/10.1038/onc.2011.485

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