Biology subjects

Nagore, E.

Publications and source records attributed to Nagore, E..

3 recordsLinked to original sources

bioRxiv2021

Ultraviolet light-induced collagen degradation inhibits melanoma invasion

Ultraviolet radiation (UVR) increases the incidence of cutaneous melanoma1-4. The ageing, sun-exposed dermis accumulates UVR damage5, and older patients develop more melanomas at UVR-exposed sites4,6,7. As fibroblasts are functionally heterogeneous and play key roles in the stromal contribution to cancer8,9, we asked whether UVR modifies dermal fibroblast function. Here we confirmed the expression of collagen-cleaving matrix metalloprotein-1 (MMP1) by UVR-damaged fibroblasts was persistently upregulated to reduce local levels of collagen 1 (COL1A1), and found dermal COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, we show inhibiting extracellular matrix degradation and MMP1 expression restored melanoma invasion to UVR damaged dermis. We confirmed in vitro findings in a cohort of primary cutaneous melanomas of aged humans, showing more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen. We found collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. These data indicate melanomas arising over UVR-damaged, collagen-poor skin of the elderly are less invasive, and this reduced invasion improves survival. Consequently, although UVR increases tumour incidence, it delays primary melanoma invasion by degrading collagen. However, we show melanoma-associated fibroblasts can restore invasion in low-collagen primary tumours by increasing collagen synthesis. Finally, we demonstrate high COL1A1 gene expression is a biomarker of poor outcome across a broad range of primary cancers.

cancer biology↗

bioRxiv2021

MOLECULAR LANDSCAPE OF OLD AGE MELANOMA BY SURVIVAL AND IMMUNOTHERAPY RESPONSE

Melanoma mortality particularly affects older patients, and age is a powerful independent predictor of death. The pathogenic mutations and transcriptomic changes associated with poor survival in aged patients are not known. We analyzed 5 cohorts of metastatic (N=324, N=18, N=66) and primary melanomas (N=103, N=30) to establish the effect of age on prognosis, identify age-specific driver genes and transcriptomic changes linked to survival and immunotherapy response. We identify the pathogenic mutations and transcriptomic changes associated with poor survival by age, and show mutations in BRAF, NRAS, CDKN2A or IDH1 identify metastatic and primary melanoma aged patients with worse outcome. In contrast, activation of immune-regulatory pathways is a hallmark of long-term survival. We tested if mutations in genes linked to poor outcome are associated to immunotherapy responders, exploring combinations of agespecific mutations in metastatic immune checkpoint inhibitor aged responders. Strikingly, aged patients with BRAF, NRAS, CDKN2A or IDH1 mutations and high tumor mutation burden treated with immunotherapy have an improved median survival of 12 months. These data highlight the molecular landscape of melanoma varies by age, and age stratification can refine prognosis and therapy rationales. A set of mutations identifies patients at highest risk of death who are likely immunotherapy responders.

cancer biology↗

bioRxiv2019

Coding and noncoding somatic mutations in basal cell carcinoma

Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of the PTCH1 and TP53 genes and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcriptions levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 59% and TP53 in 31% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59% and 38% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. TERT promoter mutations but not THOR methylation associated with an increased expression of the reverse transcriptase subunit. Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter.

cancer biology↗