Biology subjects

Macagno, N.

Publications and source records attributed to Macagno, N..

4 recordsLinked to original sources

bioRxiv2026

Spatially resolved diversity in molecular states underlies congenital melanocytic nevi and associated tumors

The congenital melanocytic nevus (CMN) is a developmental skin disorder characterized by prenatal melanocyte overgrowth, exhibiting heterogeneity in surface size, depth, and clinical behavior. Large/giant CMN carry an elevated, anticipatory melanoma risk relative to more common, small CMN. However, deeper insights into melanocytic states, genomic and epigenomic alterations, and microenvironmental cues governing disease progression are needed to predict lesions disposed to transformation. Although large/giant CMN melanocyte heterogeneity was recently established, spatial organization of these states and their niche interactions are unknown. Using advanced spatial and single-cell transcriptomics and bulk methylomics, we characterized ten CMN, seven CMN-associated proliferative nodules and three clinically diagnosed melanomas arising in CMN from children, integrating data from healthy skin references to contextualize melanocyte states in situ. CMN-specific melanocytic states, distinct in differentiation and proliferation, were spatially stratified, with immature melanocytes in deep dermis and more differentiated melanocytes approaching the epidermis. We then constructed a robust atlas of CMN cellular states by integrating single-cell transcriptomic data from five new large/giant CMN with published datasets, using it to deconvolute the spatial information. Cell-cell communication inference uncovered enhanced signaling (e.g. pleiotrophin, IGF1, periostin, semaphorin pathways) between CMN melanocytes, fibroblasts, and hair follicle-associated cells. Analysis of CMN-derived tumors, including longitudinal cases with [≥]2 samples, revealed divergent spatial melanocytic transcription distinguishing immune-enriched lesions from tumors with oncogenic/pro-invasive signatures. Collectively, these findings establish a spatially resolved framework linking melanocyte heterogeneity, signaling, and genomic instability in CMN, providing mechanistic insights to refine risk stratification and prognosis for CMN-associated tumors.

genetics↗

bioRxiv2025

RIPOR2 promotes multinucleation of melanoma cells downstream of the RAS/ERK oncogenic pathway

One-third of skin melanomas arise from melanocytic nevi, benign skin lesions composed of clustered melanocytes. Benign nevi are associated with overactivation of the mitogen-activated protein kinase RAS/ERK pathway, resulting from driver mutations, most commonly in the BRAF or NRAS gene. However, this overactivation in melanocytes is insufficient to induce melanoma formation, as only a minority of benign nevi give rise to melanoma. Overactivation of the RAS/ERK pathway promotes genetic and epigenetic alterations by inducing aneuploidy, but the processes by which nevi evolve into melanoma via RAS/ERK pathway-dependent aneuploidy are only partially understood. Using single-nucleus RNA sequencing after overactivation of the RAS/ERK pathway in the chicken embryo, we discovered that RIPOR2 is a positive transcriptional target of this pathway, including in melanocyte precursors. Similar transcriptional control of RIPOR2 by RAS/ERK is conserved in human melanoma cells. RIPOR2 emerged as an attractive target because it encodes an atypical RHOA inhibitory protein involved in the development of physiologically multinucleated cell types. Multinucleation in cancer has been shown to promote aneuploidy, which correlates with tumor aggressiveness. We found that RIPOR2 is ectopically expressed in human nevi and skin melanomas and functionally promotes multinucleation in both an animal model and human tumor-derived cells, including melanoma cell lines. Our results suggest that RIPOR2 expression, downstream of RAS/ERK overactivation in skin melanocytes, promotes the emergence of multinucleated cells, a previously overlooked step in melanoma formation.

cancer biology↗

bioRxiv2024

Deconvoluted methylation profiles discriminate between closely related melanocytic nevi

Congenital melanocytic nevi (CMN) and common acquired melanocytic nevi (AMN) are melanoma-predisposing skin conditions presenting excessive numbers of melanocytes but arising at different times in life. Appropriately weighted whole-genome methylation analysis can be used as a basis for further research in dermatopathology and as applied here provides new insights into nevus biology.

cancer biology↗

bioRxiv2022

Multiple congenital malformations arise from somatic mosaicism for constitutively active Pik3ca signalling

Recurrent missense mutations of the PIK3CA oncogene are among the most frequent drivers of human cancers. These often lead to constitutive activation of its product p110, a phosphatidylinositol 3-kinase (PI3K) catalytic subunit. In addition to causing a broad range of cancers, the H1047R mutation is also found in affected tissues of a distinct set of congenital tumors and malformations. Collectively termed PIK3CA-related disorders (PRDs), these lead to overgrowth of brain, adipose, connective and musculoskeletal tissues and/or blood and lymphatic vessel components. Vascular malformations are frequently observed in PRD, due to cell-autonomous activation of PI3K signaling within endothelial cells. These, like most muscle, connective tissue and bone, are derived from the embryonic mesoderm. However, important organ systems affected in PRDs are neuroectodermal derivatives. To further examine their development, we drove the most common post-zygotic activating mutation of Pik3ca in neural crest and related embryonic lineages. Outcomes included macrocephaly, cleft secondary palate and more subtle skull anomalies. Surprisingly, Pik3ca-mutant subpopulations of neural crest origin were also associated with widespread cephalic vascular anomalies. Mesectodermal neural crest is a major source of non-endothelial connective tissue in the head, but not the body. To examine the response of vascular connective tissues of the body to constitutive Pik3ca activity during development, we expressed the mutation by way of an Egr2 (Krox20) Cre driver. Lineage tracing led us to observe new lineages that had normally once expressed Krox20 and that may be co-opted in pathogenesis, including vascular pericytes and perimysial fibroblasts. Finally, Schwann cell precursors having transcribed either Krox20 or Sox10 and induced to express constitutively active PI3K were associated with vascular and other tumors. These murine phenotypes may aid discovery of new candidate human PRDs affecting craniofacial and vascular smooth muscle development as well as the reciprocal paracrine signaling mechanisms leading to tissue overgrowth.

developmental biology↗