You are here

| Cancer Stem Cells

New Model Highlights a Mature Cell of Origin for Melanoma

Comment

Discuss

Review of “Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes” from Cell Stem Cell by Stuart P. Atkinson

The identification of the cell-of-origin for the often-deadly cutaneous melanoma form of skin cancer may facilitate early detection of disease and the elaboration of effective treatment options. Hair follicle (HF) and interfollicular (IF) melanocyte stem cells had represented the number one suspects [1] until the publication of a new report from the laboratory of Jean-Christophe Marine (KU Leuven, Belgium). The laboratory’s new Cell Stem Cell article now establishes a more mature epidermal cell type epidermis as the target cell for melanoma initiation [2].

Kohler et al. employed a mouse model of melanoma by inducing the expression of common mutant genes in human melanoma in tail interfollicular melanocytes (BRAFV600E-oncogene and loss of the Pten tumor suppressor [3, 4]), which faithfully recapitulated the histopathological features of early stages of human melanomagenesis. 

Subsequent assessments, including single-cell lineage tracing and transcriptomic approaches with time-lapse imaging, then demonstrated to the authors that the oft-suspected stem cell populations did not give rise to tumors and instead suppressed melanoma formation. 

Surprisingly, BRafV600E expression and Pten loss triggered more mature pigment-producing melanocytes to expand, dedifferentiate to a stem cell-like state via transcriptional reprogramming, and then invade the epidermis and form melanoma tumors. This finding agrees with the recognized role of ultraviolet (UV) radiation as a trigger for melanomagenesis, given the high exposure of melanocytes to UV light at the dermo-epidermal junction.

This study provides the first in vivo proof of mature cell dedifferentiation into tumor-initiating cells, evidence that frees stem cells from their burden of guilt. The authors note that this mechanism may be at play in other cancer types and suggest that microenvironmental cues may play a more significant role in tumor predisposition than intrinsic differences in cellular origin.

To find out where this study will take cancer research next, stay tuned to the Stem Cells Portal

References

  1. Hoerter JD, Bradley P, Casillas A, et al., Does Melanoma Begin in a Melanocyte Stem Cell? Journal of Skin Cancer 2012;2012:9.
  2. Köhler C, Nittner D, Rambow F, et al., Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes. Cell Stem Cell;21:679-693.e6.
  3. Dankort D, Filenova E, Collado M, et al., A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes & Development 2007;21:379-384.
  4. Damsky WE, Curley DP, Santhanakrishnan M, et al., beta-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell 2011;20:741-54.

Review of “Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes” from Cell Stem Cell by Stuart P. Atkinson

The identification of the cell-of-origin for the often-deadly cutaneous melanoma form of skin cancer may facilitate early detection of disease and the elaboration of effective treatment options. Hair follicle (HF) and interfollicular (IF) melanocyte stem cells had represented the number one suspects

[1]

until the publication of a new report from the laboratory of Jean-Christophe Marine (KU Leuven, Belgium). The laboratory’s new Cell Stem Cell article now establishes a more mature epidermal cell type epidermis as the target cell for melanoma initiation

[2]

.

Kohler et al. employed a mouse model of melanoma by inducing the expression of common mutant genes in human melanoma in tail interfollicular melanocytes (BRAFV600E-oncogene and loss of the Pten tumor suppressor

[3, 4]

), which faithfully recapitulated the histopathological features of early stages of human melanomagenesis.

Subsequent assessments, including single-cell lineage tracing and transcriptomic approaches with time-lapse imaging, then demonstrated to the authors that the oft-suspected stem cell populations did not give rise to tumors and instead suppressed melanoma formation.

Surprisingly, BRafV600E expression and Pten loss triggered more mature pigment-producing melanocytes to expand, dedifferentiate to a stem cell-like state via transcriptional reprogramming, and then invade the epidermis and form melanoma tumors. This finding agrees with the recognized role of ultraviolet (UV) radiation as a trigger for melanomagenesis, given the high exposure of melanocytes to UV light at the dermo-epidermal junction.

This study provides the first in vivo proof of mature cell dedifferentiation into tumor-initiating cells, evidence that frees stem cells from their burden of guilt. The authors note that this mechanism may be at play in other cancer types and suggest that microenvironmental cues may play a more significant role in tumor predisposition than intrinsic differences in cellular origin.

To find out where this study will take cancer research next, stay tuned to the Stem Cells Portal.

References

1.            Hoerter JD, Bradley P, Casillas A, et al., Does Melanoma Begin in a Melanocyte Stem Cell? Journal of Skin Cancer 2012;2012:9.

2.            Köhler C, Nittner D, Rambow F, et al., Mouse Cutaneous Melanoma Induced by Mutant BRaf Arises from Expansion and Dedifferentiation of Mature Pigmented Melanocytes. Cell Stem Cell;21:679-693.e6.

3.            Dankort D, Filenova E, Collado M, et al., A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes & Development 2007;21:379-384.

4.            Damsky WE, Curley DP, Santhanakrishnan M, et al., beta-catenin signaling controls metastasis in Braf-activated Pten-deficient melanomas. Cancer Cell 2011;20:741-54.