Anatomic position determines oncogenic specificity in melanoma

Weiss, Joshua M.; Hunter, Miranda V.; Cruz, Nelly M; Baggiolini, Arianna; Tagore, Mohita; Ma, Yilun; Misale, Sandra; Marasco, Michelangelo; Simon-Vermot, Theresa; Campbell, Nathaniel R.; Newell, Felicity; Wilmott, James S.; Johansson, Peter; Thompson, John F.; Long, Georgina V.; Pearson, John V.; Mann, Graham J.; Scolyer, Richard A.; Waddell, Nicola; Montal, Emily; Huang, Ting-Hsiang; Jonsson, Philip; Donoghue, Mark T.A.; Harris, Christopher; Taylor, Barry S.; Xu, Tianhao; Chaligné, Ronan; Shliaha, Pavel V.; Hendrickson, Ronald C.; Jungbluth, Achim A.; Lezcano, Cecilia; Koche, Richard P.; Studer, Lorenz; Ariyan, Charlotte E.; Solit, David B.; Wolchok, Jedd D.; Merghoub, Taha; Rosen, Neal; Hayward, Nicholas K.; White, Richard M.

doi:10.1038/s41586-022-04584-6

Cited by 60 publications

(50 citation statements)

References 104 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7g ). In order to test whether the upregulated genes in footpad tumors are enriched in human acral melanomas, we calculated gene set variation analysis (GSVA) 46 scores using public datasets of human melanomas 47 – 49 . GSVA results show that the expression of the upregulated genes in mouse footpad tumors (footpad_up gene set) is higher in acral melanoma than in cutaneous melanoma (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma

et al. 2022

View full text Add to dashboard Cite

Acral melanoma commonly occurs in areas that are not exposed to much sunlight, such as the sole of the foot. Little is known about risk factors and mutational processes of plantar acral melanoma. Nuclear envelope rupture during interphase contributes to genome instability in cancer. Here, we show that the nuclear and micronuclear membranes of melanoma cells are frequently ruptured by macroscopic mechanical stress on the plantar surface due to weight-bearing activities. The marginal region of plantar melanoma nodules exhibits increased nuclear morphological abnormalities and collagen accumulations, and is more susceptible to mechanical stress than the tumor center. An increase in DNA damage coincides with nuclear membrane rupture in the tumor margin. Nuclear envelope integrity is compromised by the mechanosensitive transcriptional cofactor YAP activated in the tumor margin. Our results suggest a mutagenesis mechanism in melanoma and explain why plantar acral melanoma is frequent at higher mechanical stress points.

show abstract

Section: Resultsmentioning

confidence: 99%

Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma

et al. 2022

View full text Add to dashboard Cite

show abstract

“… 29 Furthermore, novel translational science approaches such as genomic sequencing and spatial transcriptomics will help elucidate more information on the relationship between the primary tumor and surrounding tumor microenvironment. 30 Dedicated trials including early phase drugs in development should be specifically designed to include patients with acral melanoma. 31 This will also allow prospective data collection and subsequent pooled analyses to be conducted, which is of particular importance in this rare cancer type.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

Bhave

Ahmed

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundAcral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.MethodsPatients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).ResultsIn total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.ConclusionWhile the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

show abstract

“…Later, to study the role of NRAS using zebrafish, transgenic human NRAS Q61K mutants were also described [ 28 ]. More recently, the relevance of the zebrafish model in melanoma research was highlighted by the identification of the loss of SPRED1 in mucosal melanoma [ 29 ] and the role of anatomical position in determining oncogenic specificity [ 30 ].…”

Section: Zebrafish As a Research Modelmentioning

confidence: 99%

Zebrafish Models to Study the Crosstalk between Inflammation and NADPH Oxidase-Derived Oxidative Stress in Melanoma

2022

View full text Add to dashboard Cite

Melanoma is the deadliest form of skin cancer, and its incidence continues to increase. In the early stages of melanoma, when the malignant cells have not spread to lymph nodes, they can be removed by simple surgery and there is usually low recurrence. Melanoma has a high mortality rate due to its ability to metastasize; once melanoma has spread, it becomes a major health complication. For these reasons, it is important to study how healthy melanocytes transform into melanoma cells, how they interact with the immune system, which mechanisms they use to escape immunosurveillance, and, finally, how they spread and colonize other tissues, metastasizing. Inflammation and oxidative stress play important roles in the development of several types of cancer, including melanoma, but it is not yet clear under which conditions they are beneficial or detrimental. Models capable of studying the relevance of inflammation and oxidative stress in the early steps of melanocyte transformation are urgently needed, as they are expected to help recognize premetastatic lesions in patients by improving both early detection and the development of new therapies.

show abstract

Anatomic position determines oncogenic specificity in melanoma

Cited by 60 publications

References 104 publications

Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma

Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

Zebrafish Models to Study the Crosstalk between Inflammation and NADPH Oxidase-Derived Oxidative Stress in Melanoma

Contact Info

Product

Resources

About