Reemergence of neural crest stem cell-like states in melanoma during disease progression and treatment

Abstract

Melanoma is the deadliest of all skin cancers due to its high metastatic potential. In recent years, advances in targeted therapy and immunotherapy have contributed to a remarkable progress in the treatment of metastatic disease. However, intrinsic or acquired resistance to such therapies remains a major obstacle in melanoma treatment. Melanoma disease progression, beginning from tumor initiation and growth to acquisition of invasive phenotypes and metastatic spread and acquisition of treatment resistance, has been associated with cellular dedifferentiation and the hijacking of gene regulatory networks reminiscent of the neural crest (NC)-the developmental structure which gives rise to melanocytes and hence melanoma. This review summarizes the experimental evidence for the involvement of NC stem cell (NCSC)-like cell states during melanoma progression and addresses novel approaches to combat the emergence of stemness characteristics that have shown to be linked with aggressive disease outcome and drug resistance.

From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

“…Melanocytes derive from neural crest stem cells (NCSCs) that disseminate into the embryo to form an array of diverse cell lineages [ 139 ]. Neural crest (NC) specification and migration modules contain critical SOX family members such as SOX9, SOX10 ( Figure 4 ), and SOX5 (WM266-4, MS: 3.07; Table S3 , [ 35 ]), together with the TFAP2(A) /AP2(A) (WM115, MS: 0.00; WM266-4, MS: 2.34; Table S1 , [ 35 ]) and RXRG (WM266-4, MS: 5.70; Table S3 [ 35 ]) program regulators [ 140 ].…”

“…Rabbit monoclonal antibodies raised against (alphabetically ordered) ATF4, ATG7, cleaved (activated) Caspase-3 (Asp175) (a-Caspase-3), DR5, HIF1α, Keratin-5, LC3B, LOX, LOXL2, N-Cadherin, p63α, PDGFRβ, p-GSK3β-Ser 9 (p-GSK3β), p-H2AX-Ser 139 (p-H2AX), p-S6-Ser 235/236 (p-S6), p-SMAD2-Ser 465/467 (p-SMAD2), SLUG, SOX2, SOX9, SOX10, Vimentin, YAP, ZEB1, and ZEB2 were purchased from Cell Signaling Technology Inc. (Danvers, MA, USA). Rabbit polyclonal antibodies recognizing (alphabetically ordered) ATG12, β-Catenin, E-Cadherin, p-AKT-Ser 473 (p-AKT), Pan-Actin, PCM1, p-p38-Thr 180 /Tyr 182 MAPK (p-p38), p-p44/42-Thr 202 /Tyr 204 MAPK (p-ERK1/2), p-p53-Ser 15 (p-p53 Ser15 ), p-p53-Ser 37 (p-p53 Ser37 ), p-SAPK/JNK-Thr 183 /Tyr 185 (p-JNK), and p-STAT3-Tyr 705 (p-STAT3) were obtained from Cell Signaling Technology Inc. (Danvers, MA, USA), while the respective ones against MCT1 and MCT4 were provided by Merck Millipore (Burlington, MA, USA).…”

Tfap2b specifies an embryonic melanocyte stem cell that retains adult multi-fate potential

“…As one of the most aggressive and heterogenous cancers, the melanoma transcriptional landscape spans developmental neural crest and melanocyte lineage signatures, stem cell signatures, and trans-differentiation signatures (Diener and Sommer, 2020;Marine et al, 2020;Patton et al, 2021). We propose that the molecular mechanisms that regulate MSC biology have direct relevance to melanoma pathogenesis.…”

“…These cell populations may be similar to the multi-potent NC-derived Schwann-cell precursor (SCP) population in chick and mouse that gives rise to melanocytes (Furlan and Adameyko, 2018). SCPs migrate ventrally from the neural crest to the DRG, and then reside along the growing nerve, representing a niche for various cell types, including melanocytes (Adameyko et al, 2009;Diener and Sommer, 2020;Ernfors, 2010). Zebrafish do not have hair, but the zebrafish MSC anatomical niche site suggests that zebrafish MSCs are functionally analogous to the SCP population found in birds and mammals (Budi et al, 2011;Dooley et al, 2013).…”

“…How melanocytes develop in embryogenesis and maintain a regenerative melanocyte population in adulthood is central to our understanding of pigmentation and pattern formation through evolution, as well as in human disease (Baxter and Pavan, 2013;Irion and Nusslein-Volhard, 2019;Kelsh and Barsh, 2011;Kinsler and Larue, 2018;Nusslein-Volhard and Singh, 2017;Parichy and Spiewak, 2015). In melanoma, a deadly cancer of the melanocyte, neural crest and melanocyte developmental mechanisms become reactivated in pathological processes driving melanoma initiation, metastasis, survival and drug resistance (Diener and Sommer, 2020;Johansson et al, 2020;Kaufman et al, 2016;Konieczkowski et al, 2014;Marie et al, 2020;Rambow et al, 2018;Shakhova et al, 2012;Travnickova et al, 2019;Varum et al, 2019;White et al, 2011). Therefore, while mechanisms that underpin neural crest and melanocyte development are important in understanding fundamental cell biology and pattern formation in the animal kingdom, in the disease context, understanding dysregulation and heterogeneity of developmental lineages in cancer provides a rich source of drug targets for the next generation of melanoma therapies (Patton et al, 2021).…”