Interferon-Alpha Decreases Cancer Stem Cell Properties and Modulates Exosomes in Malignant Melanoma
by
, , , , , , , and
María Belén García-Ortega
1,2,3,4, 
Ernesto Aparicio
1,2,3,5,
Carmen Griñán-Lisón
1,2,3,6,7,
Gema Jiménez
1,2,3,8
,
Elena López-Ruiz
2,3,9
,
José Luis Palacios
1,3,
Gloria Ruiz-Alcalá
1,2,3,
Cristina Alba
4,
Antonio Martínez
10,
Houria Boulaiz
1,2,3,8
,
Macarena Perán
1,2,3,9,
Michael Hackenberg
1,2,3,5
,
José Bragança
11,12,13
,
Sofia M. Calado
11,12,13,
Juan A. Marchal
1,2,3,8,*
and
María Ángel García
1,2,3,14,* 1
Biopathology and Regenerative Medicine Institute (IBIMER), Centre for Biomedical Research, University of Granada, 18016 Granada, Spain
2
Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), 18012 Granada, Spain
3
Excellence Research Unit “Modelling Nature” (MNat), University of Granada, 18071 Granada, Spain
4
Department of Oncology, Virgen de las Nieves University Hospital, 18014 Granada, Spain
5
Department of Genetics, University of Granada, 18100 Granada, Spain
6
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, 18011 Granada, Spain
7
GENYO-Centre for Genomics and Oncological Research-Pfizer/University of Granada/Andalusian Regional Government, 18016 Granada, Spain
8
Department of Human Anatomy and Embryology, Faculty of Medicine, University of Granada, 18016 Granada, Spain
9
Department of Health Sciences, University of Jaén, Campus de las Lagunillas SN, 23071 Jaén, Spain
10
Department of Dermatology, Virgen de las Nieves University Hospital, 18014 Granada, Spain
11
Algarve Biomedical Center Research Institute (ABC-RI), Universidade do Algarve, 8005-139 Faro, Portugal
12
Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, 8005-139 Faro, Portugal
13
Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal
14
Department of Molecular Biology and Biochemistry III and Immunology, Faculty of Medicine, University of Granada, 18016 Granada, Spain
*
Authors to whom correspondence should be addressed.
Cancers 2023, 15(14), 3666; https://doi.org/10.3390/cancers15143666
Submission received: 31 May 2023
/
Revised: 6 July 2023
/
Accepted: 15 July 2023
/
Published: 18 July 2023
(This article belongs to the Topic Cancer Stem Cells, DNA Methylation and DNA Sequences: Their Diagnostic and Therapeutical Applications)
Simple Summary
Malignant melanoma spreads to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). To combat these aggressive subpopulations, different therapies are being studied. Our study aimed to evaluate the anti-tumor effect of interferon-alpha (IFN-α) treatments on melanoma CSCs and explore potential biomarkers. We found that even low doses of IFN-α reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-α also modulated the expression of genes and microRNAs involved in several cancer processes and the metabolomics of released exosomes. Our data suggest further investigations of new dose and combination approaches with IFN-α in malignant melanoma.
Abstract
Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-α) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable side effects. In this study, we evaluated the effect of low and high doses of IFN-α on CSCs by analyzing ALDH activity, side population and specific surface markers in established and patient-derived primary cell lines. We also assessed the clonogenicity, migration and tumor initiation capacities of IFN-α treated CSCs. Additionally, we investigated genomic modulations related to stemness properties using microRNA sequencing and microarrays. The effect of IFN-α on CSCs-derived exosomes was also analyzed using NanoSight and liquid chromatography (LC-HRMS)-based metabolomic analysis, among others. Our results showed that even low doses of IFN-α reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-α also modulated the expression of genes and microRNAs involved in several cancer processes and metabolomics of released exosomes. Our work suggests the utility of low doses of interferon, combined with the analysis of metabolic biomarkers, as a potential clinical approach against the aggressiveness of CSCs in melanoma.
Keywords:
interferon-α; malignant melanoma; cancer stem cells; exosomes; metabolomics; biomarkers
