TY - JOUR
T1 - Cancer stem cells and the slow cycling phenotype
T2 - How to cut the gordian knot driving resistance to therapy in melanoma
AU - Fattore, Luigi
AU - Mancini, Rita
AU - Ciliberto, Gennaro
N1 - Funding Information:
Funding: This work was supported by: 1) Italian Association for Cancer Research (AIRC) grants IG15216 to G. Ciliberto and IG17009 to Rita Mancini; 2) the Lazioinova grant 2018 n.85-2017-13750 to Rita Mancini; 3) PRIN Bando 2017 (Prot. 2017HWTP2K) to G. Ciliberto and R. Mancini.
Funding Information:
Acknowledgments: Editorial assistance was provided by Luca Giacomelli and Aashni Shah (Polistudium SRL, Milan, Italy). This assistance was supported by internal funds.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a “phenotype switching” plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely 1) kinases and metabolic changes, 2) melanoma-associated proteins, 3) Hippo pathway and 4) slow cycling/CSCs factors. Furthermore, we show how a protein−protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma.
AB - Cancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a “phenotype switching” plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely 1) kinases and metabolic changes, 2) melanoma-associated proteins, 3) Hippo pathway and 4) slow cycling/CSCs factors. Furthermore, we show how a protein−protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma.
KW - Cancer stem cells
KW - Drug resistance
KW - Lipid metabolism
KW - Melanoma
KW - OXPHOS
KW - Slow cycling phenotype
KW - Target therapy
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U2 - 10.3390/cancers12113368
DO - 10.3390/cancers12113368
M3 - Article
AN - SCOPUS:85096070175
VL - 12
SP - 1
EP - 21
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 11
M1 - 3368
ER -