Phenotype Switching and the Melanoma Microenvironment; Impact on Immunotherapy and Drug Resistance

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Jan 21

PMID 36675114

Authors

Sultana Mehbuba Hossain

Michael R Eccles

Affiliations

Soon will be listed here.

Abstract

Melanoma, a highly heterogeneous tumor, is comprised of a functionally diverse spectrum of cell phenotypes and subpopulations, including stromal cells in the tumor microenvironment (TME). Melanoma has been shown to dynamically shift between different transcriptional states or phenotypes. This is referred to as phenotype switching in melanoma, and it involves switching between quiescent and proliferative cell cycle states, and dramatic shifts in invasiveness, as well as changes in signaling pathways in the melanoma cells, and immune cell composition in the TME. Melanoma cell plasticity is associated with altered gene expression in immune cells and cancer-associated fibroblasts, as well as changes in extracellular matrix, which drive the metastatic cascade and therapeutic resistance. Therefore, resistance to therapy in melanoma is not only dependent on genetic evolution, but it has also been suggested to be driven by gene expression changes and adaptive phenotypic cell plasticity. This review discusses recent findings in melanoma phenotype switching, immunotherapy resistance, and the balancing of the homeostatic TME between the different melanoma cell subpopulations. We also discuss future perspectives of the biology of neural crest-like state(s) in melanoma.

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References

Arozarena I, Wellbrock C . Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat Rev Cancer. 2019; 19(7):377-391. DOI: 10.1038/s41568-019-0154-4. View

Tirosh I, Izar B, Prakadan S, Wadsworth 2nd M, Treacy D, Trombetta J . Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016; 352(6282):189-96. PMC: 4944528. DOI: 10.1126/science.aad0501. View

OConnell M, Weeraratna A . Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt. Pigment Cell Melanoma Res. 2009; 22(6):724-39. PMC: 2766021. DOI: 10.1111/j.1755-148X.2009.00627.x. View

Ascierto P, Ferrucci P, Fisher R, Del Vecchio M, Atkinson V, Schmidt H . Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019; 25(6):941-946. DOI: 10.1038/s41591-019-0448-9. View

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

Derynck R, Zhang Y . Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003; 425(6958):577-84. DOI: 10.1038/nature02006. View

Bowyer S, Lee R, Fusi A, Lorigan P . Dabrafenib and its use in the treatment of metastatic melanoma. Melanoma Manag. 2018; 2(3):199-208. PMC: 6094610. DOI: 10.2217/mmt.15.21. View

Fallahi-Sichani M, Becker V, Izar B, Baker G, Lin J, Boswell S . Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol Syst Biol. 2017; 13(1):905. PMC: 5248573. DOI: 10.15252/msb.20166796. View

Giancotti F . Mechanisms governing metastatic dormancy and reactivation. Cell. 2013; 155(4):750-64. PMC: 4354734. DOI: 10.1016/j.cell.2013.10.029. View

10.

Caramel J, Papadogeorgakis E, Hill L, Browne G, Richard G, Wierinckx A . A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell. 2013; 24(4):466-80. DOI: 10.1016/j.ccr.2013.08.018. View

11.

Zhao Y, Yang W, Huang Y, Cui R, Li X, Li B . Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy. Cell Physiol Biochem. 2018; 47(2):721-734. DOI: 10.1159/000490025. View

12.

Webster M, Kugel 3rd C, Weeraratna A . The Wnts of change: How Wnts regulate phenotype switching in melanoma. Biochim Biophys Acta. 2015; 1856(2):244-51. PMC: 4668201. DOI: 10.1016/j.bbcan.2015.10.002. View

13.

Hao Y, Baker D, Ten Dijke P . TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis. Int J Mol Sci. 2019; 20(11). PMC: 6600375. DOI: 10.3390/ijms20112767. View

14.

Xu X, Garcia M, Li T, Khor L, Gajapathy R, Spittle C . Cytoskeleton alterations in melanoma: aberrant expression of cortactin, an actin-binding adapter protein, correlates with melanocytic tumor progression. Mod Pathol. 2009; 23(2):187-96. PMC: 2827925. DOI: 10.1038/modpathol.2009.157. View

15.

McGranahan N, Swanton C . Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015; 27(1):15-26. DOI: 10.1016/j.ccell.2014.12.001. View

16.

Balan V, Leicht D, Zhu J, Balan K, Kaplun A, Singh-Gupta V . Identification of novel in vivo Raf-1 phosphorylation sites mediating positive feedback Raf-1 regulation by extracellular signal-regulated kinase. Mol Biol Cell. 2006; 17(3):1141-53. PMC: 1382304. DOI: 10.1091/mbc.e04-12-1123. View

17.

Tang Y, Durand S, Dalle S, Caramel J . EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment. Cancers (Basel). 2020; 12(8). PMC: 7465730. DOI: 10.3390/cancers12082154. View

18.

Lastwika K, Wilson 3rd W, Li Q, Norris J, Xu H, Ghazarian S . Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. Cancer Res. 2015; 76(2):227-38. DOI: 10.1158/0008-5472.CAN-14-3362. View

19.

Li F, Dhillon A, Anderson R, McArthur G, Ferrao P . Phenotype switching in melanoma: implications for progression and therapy. Front Oncol. 2015; 5:31. PMC: 4327420. DOI: 10.3389/fonc.2015.00031. View

20.

Sabbatino F, Villani V, Yearley J, Deshpande V, Cai L, Konstantinidis I . PD-L1 and HLA Class I Antigen Expression and Clinical Course of the Disease in Intrahepatic Cholangiocarcinoma. Clin Cancer Res. 2015; 22(2):470-8. PMC: 5296951. DOI: 10.1158/1078-0432.CCR-15-0715. View