2. Academic Validation
  3. BGN/MDK Axis in the Melanoma Tumor Microenvironment Strengthens Tumor Malignancy by Modulating Cancer Cells and Cancer-Associated Fibroblasts Crosstalk

BGN/MDK Axis in the Melanoma Tumor Microenvironment Strengthens Tumor Malignancy by Modulating Cancer Cells and Cancer-Associated Fibroblasts Crosstalk

  • Adv Sci (Weinh). 2026 May;13(28):e14590. doi: 10.1002/advs.202514590.
Hao-Ze Shi 1,  Ming-Yang Wu 1,  Jin-Quan Liu 2,  Cuicui Tian 1,  Li Ma 3,  Xue-Mei Zhou 3,  Ze-Hao Sun 4,  Zhi-Yong Xu 4,  Run-Dong Zhang 1,  Shan-Yuan Ye 1,  Li-Ming Huang 1,  Yan Wang 1,  Jing-Shu Xiong 1,  Wen-Bo Bu 1,  Xian-Feng Cheng 1,  Jian-Fang Sun 1,  Hao Chen 1
Affiliations

Affiliations

  • 1 Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, Jiangsu, China.
  • 2 Department of Dermatology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.
  • 3 Jiangsu Cancer Hospital and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 4 Weifang People's Hospital, The First Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China.
PMID: 41833003 DOI: 10.1002/advs.202514590
Abstract

While the function of biglycan (BGN) is recognized in various cancers, its precise role and the mechanisms underlying cancer-associated fibroblasts (CAFs) formation within the melanoma tumor microenvironment (TME) remain poorly understood. Utilizing spatial transcriptomics, single-cell RNA Sequencing (scRNA-seq), vitro/vivo assays, function analysis and molecular assays, this study comprehensively investigated the BGN regulatory network. We discovered that N6-methyladenosine (m6A) modulators-specifically YTHDF3, YTHDC1, and METTL14-cooperatively upregulate BGN expression in a parallel, non-hierarchical manner converging on functional m6A sites within melanoma cells. Consequently, BGN significantly promoted melanoma proliferation and metastasis. Within the TME, spatial transcriptomics and scRNA-seq revealed that CAFs, rather than tumor cells, exhibited the highest BGN expression. Cell trajectory analysis indicated that myCAFsBGN-high may originate from iCAFsBGN-low to interact with melanoma cells. Furthermore, midkine (MDK) signaling pathways was identified by cell chat analysis. Transcriptomic and spatial analysis revealed that BGN could regulate its expression at RNA and protein levels in CAFs through the regulator AE binding protein 1 (AEBP1). And the tumor promotion effect of CAFs may be executed by BGN/MDK axis, which also reduced CD8⁺ T cell infiltration in TME. Pharmacological inhibition of MDK also suppressed tumor growth with increased CD8⁺ T cell infiltration. Finally, this BGN/MDK axis could also drive the activation of normal fibroblasts into a CAF-like phenotype verified by vitro assays. In conclusion, the interplay between Cancer cells and CAFs mediated by the BGN/MDK axis is a critical driver of malignancy in melanoma, highlighting it as a promising therapeutic target for intervention.

Keywords

biglycan (BGN); cancer‐associated fibroblasts (CAFs); melanoma; midkine (MDK); tumor microenvironment.

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