Skin Cancer and Ageing - Amaya Viros

Amaya obtained her degree in Medicine and Surgery at the University of Barcelona. She completed her training as a dermatologist and venereologist at Vall d’Hebrón University Hospital, Spain. She then obtained a Fulbright Scholarship to become a Fellow in the Department of Dermatology and Pathology at the University of California, San Francisco, in the laboratory of Boris Bastian. She then moved to Richard Marais’ laboratory, first to the Institute of Cancer Research and then at the CRUK Manchester Institute where she obtained a PhD. Amaya has combined her research with clinical work as a dermatologist at St. George’s Hospital in London, and Salford Royal Foundation Trust in Manchester. Her research has focused on the mechanisms driving secondary keratinocytic tumours in metastatic melanoma patients treated with the BRAF inhibitor vemurafenib, as well as on dissecting the specific contribution of ultraviolet radiation to distinct subtypes of melanoma defined by their driver oncogene. In 2016, she became a Wellcome Trust Intermediate Clinician Scientist Fellow and won the Wellcome-Beit Award. Her lab focuses on how ageing influences melanoma initiation and progression, and on developing rationales of adjuvant care for patients at high risk for melanoma progression. Amaya was most recently awarded the 2018 European Society for Dermatological Research Rising Star. 

Introduction

Cancer is more common in elderly patients and melanoma incidence continues to rise predominantly in this population. More than 80% of melanoma deaths occur in patients who are older than 50 years of age, and mortality is specifically increasing in the elderly. Older patients are more likely to suffer from multiple melanocytic and non-melanocytic skin cancers.

graph of average deaths per year verses age at death
Age-specific melanoma mortality rates
Data prepared by CRUK

Melanomas in the elderly more frequently present as aggressive primary lesions, thick primary tumours that predominantly comprise the high-risk primary melanoma stages (Stage IIB-IIC). The overall survival for stage IIB-IIC patients of all ages at 5 years is 60% and 45%, respectively, despite being localised to the skin and non-metastatic at diagnosis. There is a gradual decline in 5-year survival with increasing decades of life, with an almost 20% decrease from ages 60 to 69, to ages greater than 80 years. Additional characteristics of poor prognosis, such as ulceration and elevated mitotic rate, are also more common in the elderly.

 

However, even after taking the main prognostic factors into account there is a survival discrepancy between elderly and young patients, and age is the strongest independent adverse prognostic factor together with tumour thickness.

Understanding the mechanisms that drive poor outcome in the elderly represents a critical current problem in melanoma care. We focus our research on understanding the changes in aged skin that promote melanoma and the biology of aggressive disease affecting the elderly, in order to identify new strategies of adjuvant therapy.

Changes in melanomas that drive more aggressive disease

 

The Skin Cancer and Ageing lab investigates why skin cancer is more common and more deadly in elderly patients. The incidence and mortality rates continue to rise, as does the proportion of the population who is over 50 years old. Most skin cancer deaths and skin cancer complications affect the elderly, and mortality due to skin cancer is specifically increasing in the elderly.

 

Older patients are more likely to suffer from multiple melanocytic and non-melanocytic skin cancers. We study the survival discrepancy between elderly and young patients, as age is a strong independent adverse prognostic factor. Lately, our group has focused on understanding the changes in melanomas that drive more aggressive disease.

 

Histological image showing the cutaneous papilloma from a female mouse following exposure to the carcinogen DMBA/TPA.

 

Impact of age and sex on melanoma growth

 

We found that age and sex determine melanoma mutation rate, and we used mathematical approaches to model how age-mutations and sun-mutations accumulate by sex and age in melanoma. Similar to aged healthy, homeostatic tissues, we found that melanoma genomes decline in cell division with age. Critically, UV damage increases cell division, but the effect of UV on cell division was more pronounced in men. Thus, we discovered that males present more mutations independently of UV damage (Lotz et al, British Journal of Dermatology 2021).

 

We have also worked on the higher incidence of skin cancer in aged men compared to aged women, and undertaken first experiments to identify new strategies of adjuvant therapy. Specifically, we published that men and male mice are more susceptible to primary aggressive and metastatic cutaneous squamous cell carcinoma (SCC). We discovered that when female and male animals are challenged with the same dose of carcinogen, they have different transcriptomic responses.

 

Critically, although both females and males repair the DNA damage from the carcinogen at equal rates, women and female mice activate distinct transcriptomic pathways linked to improved cancer immunity. We were able to validate these findings in mice and humans and showed that immunosuppressed women and mice have a similar course of disease to immunocompetent men. This work has had significant impact in the media and publication was selected for the cover of the Clinical Cancer Research June 2021 issue (Budden et al, Clinical Cancer Research 2021).

 

Histological image showing the cutaneous papilloma from a female mouse following exposure to the carcinogen DMBA/TPA. This image featured on the front cover of journal Clinical Cancer Research (June 2021, Volume 27, Issue 11).

 

Impact of growth rate

 

In addition, we have focused on the genetic changes of the melanoma cell that make a tumour more aggressive. We found that a rapid rate of growth of primary melanoma, as observed by the patient, predicts poor survival; and described the molecular, epidemiological and clinical data of 200 cases of fast and slow growth melanoma cases with long term outcome. We found distinct mutations and environmental factors in the primary tumours and patients that identified the individuals at high risk of death (Gaudy et al, Journal of the American Academy of Dermatology 2021).

 

Inhibition of collagen-cleaving matrix metalloprotein-1 (MMP1) restores melanoma invasion. Immunofluorescence of fibronectin fibres without UV radiation. Nature Communications 12(1):2742.

 

Impact of the microenvironment on melanoma development

 

Our group has focused on the features of the tumour microenvironment that affect melanoma outcome in the elderly population. We found collagen degradation in the aged dermis, following chronic UV exposure and damage to the connective tissue, inhibits melanoma invasion. We discovered collagen is necessary for primary melanoma cells to invade into the dermis.

 

Thus, we found that melanomas that arise over sun damaged skin tend to have a better outcome. There is a clear exception to this rule in aged patients who upregulate new collagen synthesis and have a particularly bad outcome. We linked the ability to synthesise new collagen in some aged tumours to a greater presence of melanoma associated fibroblasts. Patients with new collagen thus die quickly of melanoma, and we showed this in multiple clinical cohorts measuring melanoma cell invasion, collagen synthesis and melanoma specific survival. Critically, we found other primary cancers expressing high collagen have a poor outcome as well in a pan cancer analysis using TCGA data (Budden et al, Nature Communications 2021).

Selected Publications 

 

Budden T, Gaudy, C, Porter A, Kay E, Gurung S, Earnshaw C, Roeck K, Craig S, Traves V, Kruttmann J, Muller PAJ, Motta L, Zanivan S, Malliri A, Furney S, Viros A. (2021)
Ultraviolet light-induced collagen degradation inhibits melanoma invasion.
Nature Communications 12, 2742. Article

Budden T, Gaudy-Marqueste C, Craig S, Hu Y, Earnshaw CH, Gurung S, Ra A, Akhras V, Shenjere P, Green R, Jamieson L, Lear J, Motta L, Caulín C, Oudit D, Furney SJ, Virós A. (2021)
Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.
Clin Cancer Res. Online ahead of print. PubMed abstract (PMID: 33795258)

Lotz M, Budden T, Furney SJ, Virós A. (2021)
Molecular subtype, biological sex and age shape melanoma tumour evolution.
British Journal of Dermatology 184(2):328-337. PubMed abstract (PMID: 32282938)

Craig S, Virós A. (2020)
New biomarkers improve stratification of patients with melanoma.
British Journal of Dermatology 182(1):5-6. Article

Trucco LD, Mundra PA, Hogan K, Garcia-Martinez P, Viros A, Mandal AK, Macagno N, Gaudy-Marqueste C, Allan D, Baenke F, Cook M, McManus C, Sanchez-Laorden B, Dhomen N, Marais R. (2019)
Ultraviolet radiation-induced DNA damage is prognostic for outcome in melanoma.
Nature Medicine 25(2):221-224. PubMed abstract

Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, Larkin J, Marais R, Sahai E. (2015)
Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling.
Cancer Cell 27(4):574-88. PubMed abstract

Pedersen M*, Viros A*, Cook M, Marais R. (2014)
(G12D) NRAS and kinase-dead BRAF cooperate to drive naevogenesis and melanomagenesis.
Pigment Cell & Melanoma Research 27(6):1162-6. *Authors contributed equally PubMed

Viros A, Sanchez-Laorden B, Pedersen M, Furney SJ, Rae J, Hogan K, Ejiama S, Girotti MR, Dhomen N, Marais R. (2014)
Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.
Nature 511(7510):478-82. PubMed abstract

Pedersen M, Küsters-Vandevelde HV, Viros A, Groenen PJ, Sanchez-Laorden B, Gilhuis JH, van Engen-van Grunsven IA, Renier W, Schieving J, Niculescu-Duvaz I, Springer CJ, Küsters B, Wesseling P, Blokx WA, Marais R. (2013)
Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes.
Cancer Discovery 3(4):458-69. PubMed abstract

Viros A, Hayward R, Martin M, Yashar S, Yu CC, Sanchez-Laorden B, Zambon A, Niculescu-Duvaz D, Springer C, Lo RS and Marais R. (2013)
Topical 5-fluorouracil elicits regressions of BRAF inhibitor-induced cutaneous squamous cell carcinoma.
Journal of Investigative Dermatology 133(1):274-6. PubMed

Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. (2012)
RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.
New England Journal of Medicine 366(3):207-15. PubMed abstract

 

 

Postdoctoral Fellow
Tim Budden

Clinical Fellow
Sarah Craig

Graduate Students
Shilpa Gurung
Pedro Durao

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