Biology subjects

Budden, T.

Publications and source records attributed to Budden, T..

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

Female immunity protects from cutaneous squamous cell carcinoma

PurposeCancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women are more protected from aggressive cutaneous squamous cell carcinoma (cSCC) due to strong immune activation. MethodsWe explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients (N= 738, N=160) with carcinoma cSCC, in FVB/N mice exposed to equal doses of DMBA, and in human keratinocytes by whole exome sequencing, bulk and single cell RNA sequencing. ResultsWe show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations. In contrast, males increase the rate of mitoses and proliferation in response to carcinogen. Human female skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. ConclusionsThis work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity.

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↗