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.