Secretome from senescent melanoma engages the STAT3 pathway to favor reprogramming of naive melanoma towards a tumor-initiating cell phenotype
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// Mickaël Ohanna 1,2,* , Yann Cheli 1,2,* , Caroline Bonet 1,2 , Vanessa F Bonazzi 4 , Marylin Allegra 1,3 , Sandy Giuliano 1,2 , Karine Bille 1,2 , Philippe Bahadoran 1,2,3 , Damien Giacchero 3 , Jean Philippe Lacour 2,3 , Glen M Boyle 4 , Nicholas F Hayward 4 , Corine Bertolotto 1,2,* and Robert Ballotti 1,2,3,* . 1 Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome. Equipe labellisée Ligue 2013, Nice, F-06204, France 2 Université de Nice Sophia-Antipolis, UFR Médecine, Nice, F-06107, France 3 Centre Hospitalier Universitaire, Service de Dermatologie, Nice, F-06204, France 4 Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane 4006, Australia * These authors equally contributed to the work Correspondence: Robert Ballotti, email: // Keywords : melanoma, senescence, secretome, STAT3 Received : June 30, 2013 Accepted : August 17, 2013 Published : August 19, 2013 Abstract Here, we showed that the secretome of senescent melanoma cells drives basal melanoma cells towards a mesenchymal phenotype, with characteristic of stems illustrated by increased level of the prototype genes FN1, SNAIL, OCT4 and NANOG. This molecular reprogramming leads to an increase in the low-MITF and slow-growing cell population endowed with melanoma-initiating cell features. The secretome of senescent melanoma cells induces a panel of 52 genes, involved in cell movement and cell/cell interaction, among which AXL and ALDH1A3 have been implicated in melanoma development. We found that the secretome of senescent melanoma cells activates the STAT3 pathway and STAT3 inhibition prevents secretome effects, including the acquisition of tumorigenic properties. Collectively, the findings provide insights into how the secretome of melanoma cells entering senescence upon chemotherapy treatments increases the tumorigenicity of naïve melanoma cells by inducing, through STAT3 activation, a melanoma-initiating cell phenotype that could favor chemotherapy resistance and relapse.
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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 [54]
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 [54]
In vitro, co-culture experiments showed that SASP induced the expression of critical reprogramming factors NANOG, SOX2, and OCT4.
“In vitro, co-culture experiments showed that SASP induced the expression of critical reprogramming factors NANOG, SOX2, and OCT4.54”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [54]
Non-tumourigenic melanoma cells exposed to IL6 or chemokine ligand-2 (CCL2) develop tumourigenic potential in vivo in a STAT3-dependent manner.
“For instance, non-tumourigenic melanoma cells exposed to IL6 or chemokine ligand-2 (CCL2) develop tumourigenic potential in vivo in a STAT3-dependent manner.54”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [54]
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- Authors
- Ohanna, M., Cheli, Y., Bonet, C., Bonazzi, V. F., Allegra, M., Giuliano, S., Bille, K., Bahadoran, P., Giacchero, D., Lacour, J. P., Boyle, G. M., Hayward, N. F., Bertolotto, C., & Ballotti, R.
- Affiliations
- Inserm (FR)
- Inserm U1065, Centre Méditerranéen de Médecine Moléculaire, Equipe 1, Biologie et pathologies des mélanocytes: de la pigmentation cutanée au mélanome. Equipe labellisée Ligue 2013, Nice, F-06204, France
- QIMR Berghofer Medical Research Institute (AU)
- Centre Hospitalier Universitaire de Nice (FR)
- Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane 4006, Australia
- Corresponding author
- Bertolotto, Corine
- Ballotti, Robert
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2013-08-19
- Volume
- 4
- Issue
- 12
- Pages
- 2212-2224
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC3926821
- OpenAlex
- W1603365851
- Cited by
- 78
- References
- 44
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 6 · 2020: 17 · 2019: 5 · 2018: 8 · 2017: 9 · 2016: 10 · 2015: 3 · 2014: 9
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Association pour la Recherche sur le Cancer
- Science Foundation Ireland
- Institut National de la Santé et de la Recherche Médicale (U1065)
- Ligue Contre le Cancer
- Institut National Du Cancer
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, cellular senescence, secretome, STAT3 signaling, cancer stem cells, stemness, AXL, ALDH1A3, tumor microenvironment, melanoma progression, STAT3 inhibition, cell migration, cell-cell interactions, Nanog, Oct4, snails, FN1, aldehyde dehydrogenase
- MeSH terms
- Animals, Female, Humans, Melanoma, Mice, Nude, Phenotype, Random Allocation, Transfection, Neoplastic Stem Cells, Signal Transduction, Gene Expression Regulation, Neoplastic, Cellular Senescence, Xenograft Model Antitumor Assays, RNA, Small Interfering, Cell Line, Tumor, Cell Growth Processes, STAT3 Transcription Factor, Mice
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