The journey from melanocytes to melanoma

Centeno, Patricia P.; Pavet, Valeria; Marais, Richard

doi:10.1038/s41568-023-00565-7

Cited by 37 publications

(35 citation statements)

References 251 publications

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“…Moreover, mice carrying spontaneous or targeted mutations of Sox10 lack satellite glia and Schwann cells and exhibit pigmentation defects but neurogenesis is initially unaffected 64 . Furthermore, melanoma progression from normal pigment cells is accompanied by a de-differentiation state in which melanocytic markers such as DCT and MITF are downregulated and glial/melanoblast markers are instead upregulated 65 .…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid, an essential component of the RP organizer, promotes the spatio-temporal segregation of dorsal neural fates

Rekler,

Ofek,

Kagan

et al. 2024

Preprint

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Dorsal neural tube-derived retinoic acid promotes the end of neural crest production and transition into a definitive roof plate. Here we analyze how this impacts the segregation of central and peripheral lineages, a process essential for tissue patterning and function. Localized in-ovo inhibition of retinoic acid activity followed by single cell transcriptomics unraveled a comprehensive list of differentially expressed genes relevant to these processes. Importantly, progenitors co-expressed neural crest, roof plate and dI1 interneuron markers indicating a failure in proper lineage segregation. Furthermore, we found that separation between roof plate and dI1 interneurons is mediated by Notch activity downstream of retinoic acid, highlighting their critical role in establishing the roof plate-dI1 boundary. Within the peripheral branch, where absence of retinoic acid resulted in neural crest production and emigration extending into the roof plate stage, sensory progenitors failed to separate from melanocytes leading to formation of a common glia-melanocyte cell with aberrant migratory patterns. Together, we uncover and characterize a molecular mechanism responsible for segregation of dorsal neural fates during development.

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Section: Discussionmentioning

confidence: 99%

Retinoic acid, an essential component of the RP organizer, promotes the spatio-temporal segregation of dorsal neural fates

Rekler,

Ofek,

Kagan

et al. 2024

Preprint

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“…Melanoma is a malignant skin tumor that develops from genetic mutations in specific cells of melanocytes . Staged according to its degree of progression, an idealized progression model usually implies a single evolutionary path from nevus to dysplastic nevus to melanoma in situ to aggressive melanoma.…”

Section: Advances In Theoretical Research On Cancer Vaccinesmentioning

confidence: 99%

“…Melanoma is a malignant skin tumor that develops from genetic mutations in specific cells of melanocytes. 191 Staged according to its degree of progression, an idealized progression model usually implies a single evolutionary path from nevus to dysplastic nevus to melanoma in situ to aggressive melanoma. Characterized by early metastasis, high invasiveness, and poor prognosis, its incidence and mortality rates vary by country and increase with age.…”

Section: Advances In Theoretical Research On Cancer Vaccinesmentioning

confidence: 99%

Advances in Cancer Vaccine Research

Liu,

Xiao,

Zhang

et al. 2023

ACS Biomater. Sci. Eng.

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The use of cancer vaccines is considered a promising therapeutic strategy in clinical oncology, which is achieved by stimulating antitumor immunity with tumor antigens delivered in the form of cells, peptides, viruses, and nucleic acids. The ideal cancer vaccine has many advantages, including low toxicity, specificity, and induction of persistent immune memory to overcome tumor heterogeneity and reverse the immunosuppressive microenvironment. Many therapeutic vaccines have entered clinical trials for a variety of cancers, including melanoma, breast cancer, lung cancer, and others. However, many challenges, including single antigen targeting, weak immunogenicity, off-target effects, and impaired immune response, have hindered their broad clinical translation. In this review, we introduce the principle of action, components (including antigens and adjuvants), and classification (according to applicable objects and preparation methods) of cancer vaccines, summarize the delivery methods of cancer vaccines, and review the clinical and theoretical research progress of cancer vaccines. We also present new insights into cancer vaccine technologies, platforms, and applications as well as an understanding of potential next-generation preventive and therapeutic vaccine technologies, providing a broader perspective for future vaccine design.

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“…The prevalence of BRAF mutations, paucity of effective clinical approaches for late-stage disease, and poor prognosis made BRAF -mutant metastatic ideal for early adoption of novel small molecules such as vemurafenib, which selectively targets the BRAFV600E oncoprotein 8 . While targeted BRAF inhibition with vemurafenib or dabrafenib, or combined BRAF and MEK1/2 inhibitors (vemurafenib/trametinib, dabrafenib/cobimetinib or encorafenib/binimetinib) are now mainstays of the management of metastatic melanoma, the emergence of therapeutic resistance poses a significant clinical challenge 9 , and calls for new strategies targeting therapeutic resistance, melanoma recurrence, and metastatic progression (Fig 1A).…”

Section: Introductionmentioning

confidence: 99%

A targetable PREX2/RAC1/PI3Kβ signalling axis confers resistance to clinically relevant therapeutic approaches in melanoma

Ford,

Koludrovic,

Centeno

et al. 2024

Preprint

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Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identifiedbona fideactivating mutations inRAC1, with mutations of its upstream regulator, the RAC-GEFPREX2, also commonly detected. Crucially,RAC1mutations are associated with resistance to BRAF-targeting therapies. Despite the role of its homologue PREX1 in melanomagenesis, and evidence that some truncatingPREX2mutations drive increased RAC1 activity, no hotspot mutations have been identified, and the impact ofPREX2mutation remains contentious. Here, we use genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. We show that while PREX2 is dispensable for the initiation and progression of melanoma, its loss confers sensitivity to clinically relevant therapeutics. Importantly, genetic and pharmacological targeting of the RAC1 effector kinase PI3Kβ phenocopiesPREX2loss, sensitizing our model systems to therapy. Our data reveal a druggable PREX2/RAC1/PI3Kβ signalling axis inBRAF-mutant melanoma that could be exploited clinically.Statement of SignificanceMetastatic melanoma remains both a clinical problem, and an opportunity for therapeutic benefit. Co-targeting of the MAPK pathway and the PREX2/RAC1/PI3Kβ has remarkable efficacy and outperforms monotherapy MAPK targetingin vivo.

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The journey from melanocytes to melanoma

Cited by 37 publications

References 251 publications

Retinoic acid, an essential component of the RP organizer, promotes the spatio-temporal segregation of dorsal neural fates

Retinoic acid, an essential component of the RP organizer, promotes the spatio-temporal segregation of dorsal neural fates

Advances in Cancer Vaccine Research

A targetable PREX2/RAC1/PI3Kβ signalling axis confers resistance to clinically relevant therapeutic approaches in melanoma

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