Biology subjects

Marais, R.

Publications and source records attributed to Marais, R..

4 recordsLinked to original sources

bioRxiv2025

Epidermal tumour-resistant progenitors require SOX2-driven developmental reprogramming to drive tumorigenesis

The skin undergoes continuous renewal, relying on stem and progenitor cells to maintain its barrier function. Over time, multiple oncogenic and tumour suppressor events accumulate. How the skin tolerates these mutations in different populations and how cutaneous squamous cell carcinoma (cSCC) emerges from mutant clones is poorly understood. Rapid cSCC development can ensue in melanoma patients treated with BRAF inhibitors (BRAFi) through paradoxical activation of RAF signalling. To model this in mice, we induced MAPK hyperactivation in two epidermal basal populations: stem-cell-like (K14/K5+) and differentiation-committed (IVL+) cells. Remarkably rapid tumorigenesis ensued from the K14/K5+ basal population defining them as a tumour primed. In contrast, despite mutations being retained and populating the skin, IVL+ cells exhibited tumour resistance with long latency. Nevertheless, both populations can act as cSCC cells of origin. Once transformed, they share histological and transcriptomic hallmarks of epidermal transformation independently of the cell-of-origin or the oncogenic driving mutations. Critically, the pioneer factor SOX2 was uniquely upregulated in tumours arising from the resistant population and was both necessary and sufficient for their transformation. Notably, SOX2 bestow an embryonic profile to human keratinocytes and is expressed in [~]20% of human cSCC, suggesting that it could mark tumours originating from committed progenitors. HighlightsO_LIParadoxical MAPK signalling activation is a tumour promoter in cSCC C_LIO_LIK14/K5+ represent a tumour-primed population and IVL+ represents a tumour-resistant population, but both can initiate skin cancer C_LIO_LIOncogene-expressing tumour-resistant population takes over the entire skin epidermis but preserves homeostasis C_LIO_LISOX2 is sufficient to initiate cSCC from the tumour-resistant population by preventing delamination and differentiation and promoting stemness C_LI

cancer biology↗

bioRxiv2023

ALDH1A3-acetaldehyde re-wires neural crest stem cell and high metabolism states to potentiate melanoma heterogeneity

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-CoA synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest lineage and glucose metabolism genes. Importantly, we show acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3, dependent manner providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish model of melanoma residual disease, a subpopulation of ALDH1-high cells emerges following BRAF inhibitor treatment and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma. HighlightsO_LIALDH1A3-high melanomas are in a high glucose metabolic flux and neural crest stem cell dual state. C_LIO_LINuclear ALDH1A3 partners with ACSS2 to promote selective acetyl-histone H3. C_LIO_LIAcetaldehyde is an acetyl source for ALDH1A3 dependent histone H3 acetylation. C_LIO_LIALDH1A3 is a master regulator and pharmaceutical target for melanoma heterogeneity. C_LI

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↗

bioRxiv2018

Signaling pathway screening platforms are an efficient approach toidentify therapeutic targets in precision-medicine oriented early phaseclinical trials

Precision medicine aims to tailor cancer therapies to target specific tumorpromoting aberrations. For tumors that lack actionable drivers, extensive molecular characterization and pre-clinical drug efficacy studies will be required to match patients with the appropriate targeted therapy. A cell line maintained at low passage and a patient-derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patients DNA; however, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. Consistent with amplification of these genes, pathway analysis revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis complements next-generation sequencing approaches for detection of actionable alterations and will aid in patient stratification into early-phase clinical trials.

clinical trials↗