SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells.
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.
Translational Oncogenomic Unit, Italian National Cancer Institute Regina Elena, Rome, Italy.
C
C
Canino
F
F
Mori
A
A
Cambria
A
A
Diamantini
S
S
Germoni
G
G
Alessandrini
G
G
Borsellino
R
R
Galati
L
L
Battistini
R
R
Blandino
F
F
Facciolo
G
G
Citro
S
S
Strano
P
P
Muti
G
G
Blandino
M
M
Cioce
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D011905:Genes, ras / Q000235:genetics; D005971:Glutamates / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008934:Mitogens / Q000378:metabolism; D000068437:Pemetrexed; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D017077:Culture Media, Conditioned; D016207:Cytokines; D005971:Glutamates; D008934:Mitogens; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D000068437:Pemetrexed; D006147:Guanine; D000444:Aldehyde Dehydrogenase