SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells
Open accessAbstract
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.
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The SASP is able to inhibit differentiation both in vitro and in vivo, while in some cases leads to acquisition of stem cell characteristics.
“Interestingly, the SASP is able to inhibit differentiation both in vitro and in vivo, while in some cases leads to acquisition of stem cell characteristics.41,44,54,55,64–66”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [55]
Conditioned media from senescent cells can induce EMT in cell lines derived from many tumour types, including non-aggressive breast cancer, mesothelioma, and melanoma, as evidenced by decreased expression of epithelial markers and increased expression of mesenchymal markers.
“Importantly, it is known that conditioned media from senescent cells can induce EMT in cell lines derived from many tumour types, including non-aggressive breast cancer, mesothelioma, and melanoma, as evidenced by decreased expression of epithelial markers (e.g. E-cadherin, cytokeratins) and increased expression of mesenchymal markers (e.g. vimentin).12,54,55”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [55]
Induction of senescence and SASP in mesothelioma cells led to the emergence of a subpopulation of highly clonogenic cells with enhanced ability to form tumours when xenografted in mice.
“In addition, induction of senescence and SASP in mesothelioma cells led to the emergence of a subpopulation of highly clonogenic cells with enhanced ability to form tumours when xenografted in mice.55”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [55]
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- Authors
- Canino, C., Mori, F., Cambria, A., Diamantini, A., Germoni, S., Alessandrini, G., Borsellino, G., Galati, R., Battistini, L., Blandino, R., Facciolo, F., Citro, G., Strano, S., Muti, P., Blandino, G., & Cioce, M.
- Affiliations
- Instituto Nazionale Tumori Regina Elena (IT)
- Fondazione Santa Lucia (IT)
- Corresponding author
- Blandino, G
- Cioce, M
- ORCID
- Venue
- Oncogene
- Published
- 2011-10-24
- Volume
- 31
- Issue
- 26
- Pages
- 3148-3163
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2004196283
- Cited by
- 200
- References
- 50
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 18 · 2023: 15 · 2022: 18 · 2021: 25 · 2020: 17 · 2019: 16 · 2018: 14 · 2017: 4 · 2016: 18 · 2015: 15 · 2014: 8 · 2013: 7 · 2012: 4
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- Istituto Nazionale per l'Assicurazione Contro Gli Infortuni sul Lavoro
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- senescence-associated secretory phenotype, malignant pleural mesothelioma, chemoresistance, epithelial-mesenchymal transition, aldehyde dehydrogenase, cancer stem cells, pemetrexed, STAT3, RasV12, p53, cellular senescence, tumor microenvironment, cytokines, NOD/SCID xenograft
- MeSH terms
- Pemetrexed, Aldehyde Dehydrogenase, Animals, Cell Count, Cell Survival, Cell Transformation, Neoplastic, Glutamates, Guanine, Humans, Male, Mesoderm, Mesothelioma, Mitogens, Phenotype, Genes, ras, Signal Transduction, Gene Expression Regulation, Neoplastic, Cytokines, Cellular Senescence, Culture Media, Conditioned, Drug Resistance, Neoplasm, RNA, Small Interfering, Cell Line, Tumor, STAT3 Transcription Factor, Mice, Gene Knockdown Techniques, Epithelial-Mesenchymal Transition
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