spatial-temporal-control-murine-melanoma-initiation-from-mutant

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Cutaneous melanoma is well known as the most aggressive skin cancer. Although the risk factors and major genetic alterations continue to be documented ...

Cornell University

The relationship between melanocyte stem cells (MCSCs) and melanoma has been unclear. We recently demonstrated that melanoma-prone MCSCs are able to initiate cutaneous melanoma following stem cell activation through ultraviolet-B (UVB) exposure or natural stem cell cycling. Conversely, MCSC quiescence is sufficient to suppress tumorigenesis. This provides new insight into the role of environmental factors in tumor initiation from adult stem cells.

A path from melanocyte stem cells to cutaneous melanoma illuminated by UVB.

Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for Braf -mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (Tyr ; Braf ; Pten ) to Sirt5 knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5 mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for Braf -mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor.

Sirt5 is dispensable for Braf -mediated cutaneous melanoma development and growth in vivo.

The effective prevention of tumor initiation, especially for potentially inoperable tumors, will be beneficial to obtain an overall higher quality of our health and life. Hence, thorough understanding of the pathophysiological mechanisms of early tumor formation arising from identifiable cellular origins is required to develop efficient preventative and early treatment options for each tumor type. Here, using genetically engineered mouse models, we provide preclinical experimental evidence for a long-standing open question regarding the pathophysiological potential of a microenvironmental and physiological stressor in tumor development, gastric acid-mediated regional microscopic injury in foregut squamous epithelia. This study demonstrates the association of gastric acid stress with Cyclooxygenase-2-dependent tumor formation originating from tumor-competent Krt5/Krt15 foregut basal progenitor cells. Our findings suggest that clinical management of microenvironmental stressor-mediated microscopic injury may be important in delaying tumor initiation from foregut basal progenitor cells expressing pre-existing tumorigenic mutation(s) and genetic alteration(s).

Article	Year
A path from melanocyte stem cells to cutaneous melanoma illuminated by UVB. Molecular & cellular oncology\| PubMed ID: 29487896	2018
Sirt5 is dispensable for Braf -mediated cutaneous melanoma development and growth in vivo. Experimental dermatology\| PubMed ID: 30471144	2019
Krt5/Krt15 foregut basal progenitors give rise to cyclooxygenase-2-dependent tumours in response to gastric acid stress. Nature communications\| PubMed ID: 31110179	2019

Hyeongsun Moon

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