Ultraviolet light-induced collagen degradation inhibits melanoma invasion
Budden, Timothy Gaudy, C. Nagore, E Viros, Amaya
Budden, Timothy
Gaudy, C.
Nagore, E
Viros, Amaya
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Abstract
Ultraviolet radiation (UVR) increases the incidence of cutaneous melanoma. The ageing, sunexposed
dermis accumulates UVR damage, and older patients develop more melanomas at
UVR-exposed sites. As fibroblasts play key roles in the stromal response to UVR and in cancer
progression, we investigated how long term UVR modifies dermal fibroblast function and
how this affects melanoma invasion. Chronic UVR exposure on dermal fibroblasts showed
that extracellular matrix pathways, particularly those involved in collagen catabolism, were
upregulated in the absence of acute UVR. Importantly, the expression of collagen-cleaving
matrix metalloprotein-1 (MMP1) was persistently upregulated. This resulted in persistent
degradation of collagen 1, and an overall degraded and disorganised matrix. Collagen
degradation by MMP1 decreased melanoma invasion in vitro. Conversely, both inhibiting
extracellular matrix degradation and MMP1, or higher collagen 1 expression, restored the
invasion of melanoma through collagen. Primary cutaneous melanomas of aged humans
confirmed these in vitro findings, revealing significantly fewer cancer cells invade as single
cells at the invasive front of melanomas arising in chronic sun damaged skin. We show high
collagen deposition and melanoma cell invasion in the dermis are robust predictors of poor
melanoma-specific survival in 3, international cohorts of primary melanoma. Thus, melanomas
arising over UVR-damaged, collagen-poor skin are less invasive, and this reduced
invasion improves survival. However, we discovered a subset of melanomas arising over
collagen-poor, UVR-damaged dermis have a poor outcome, and found that increased new
collagen synthesis by melanoma-associated fibroblasts at the invasive front in these cases
restores melanoma single cell invasion and drives poor outcome. Finally, we demonstrate
high COL1A1 gene expression is an early stage biomarker of poor outcome across a broad
range of primary cancers.
Description
Date
2021
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Budden T, Viros A, Gaudy C, Nagore E. 081 Ultraviolet light-induced collagen degradation inhibits melanoma invasion. Journal of Investigative Dermatology. 2021;141(5).