VCAN

Overview

VCAN (versican) is a large extracellular matrix chondroitin sulfate proteoglycan involved in cell adhesion, proliferation, and migration. It is expressed in neural-crest-derived tissues and smooth-muscle-rich environments. In melanocyte biology, VCAN is a transcriptomic marker of the low-UV-burden (LowMut) neural-crest/stem-like melanocyte subpopulation, which carries predominantly clock-like mutational signatures rather than UV-attributable damage.

Alterations observed in the corpus

  • VCAN is transcriptionally upregulated in LowMut melanocytes (bottom UV-burden quartile) compared to HighMut melanocytes in a single-melanocyte multi-omics study (297 clonally-expanded cells, 31 donors; G&T-Seq + SMART-Seq2 + 10X Xenium spatial transcriptomics) PMID:39975212.
  • VCAN expression is part of the LowMut “connective-tissue/neural-crest” gene signature (along with FBN1, PALLD, ITM2A, TAGLN, MYL9, MYLK, SGCE, HACD1, SEMA3C, TCF4, DAAM2, RGMB, NTNG1), which recapitulates broader neural-crest lineage fates PMID:39975212.
  • Cross-atlas alignment places VCAN-high LowMut cells in correspondence with “melanocyte stem cell (MSC)” signatures from fetal hair-follicle-derived cells (Belote et al. 2021) and with the “AXL/Neuronal/Invasive” melanocyte states in the WIMMS framework PMID:39975212.
  • VCAN–IL23R fusion detected in a pediatric inflammatory myofibroblastic tumor (IMT) patient; identified as a JAK-inhibitor target and treated accordingly PMID:28007021

Cancer types (linked)

  • SKIN — VCAN marks the LowMut/stem-like subpopulation in normal cutaneous melanocytes, including those from non-lesional skin adjacent to melanoma; no direct oncogenic driver role is established in the current corpus PMID:39975212.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • No direct therapeutic targeting of VCAN is described in this corpus. The LowMut/neural-crest state marked by VCAN is hypothesized to represent a UV-protected reservoir for melanocyte homeostasis — potentially co-optable for tissue-rejuvenation strategies — but no validated therapeutic intervention is reported PMID:39975212.

Open questions

  • Whether VCAN-high melanocytes preferentially localize to the hair follicle bulge in situ (proposed but not directly lineage-traced in humans) remains to be established PMID:39975212.
  • VCAN’s role in the invasive/AXL melanocyte state that shares transcriptomic similarity with melanoma invasive programs raises the question of whether LowMut VCAN-high cells are a reservoir for melanoma with low UV-mutation burden PMID:39975212.

Sources

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