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<p>Most solid tumors invade peritumoral tissues as multicellular units while maintaining cell-cell interactions and epithelial characteristics, a process known as collective invasion. Our previous proteomic analysis revealed that S100-family proteins were upregulated in the PDAC secretome. Therefore, we aimed to elucidate the functional roles of these proteins in collective invasion and PDAC metastasis. To this end, we established a 3D collective invasion model using co-culture spheroids composed of PDAC cells and pancreatic stellate cells (PSCs). Using this model, we found that S100A4 contributes to collective invasion by mediating PDAC cell-PSC interactions, with S100A4 knockdown inhibiting collective invasion and S100A4 overexpression promoting it. Additionally, depletion of S100A in PDAC cells reduced trans-endothelial migration and cancer cell adhesion to endothelial cells. Mechanistically, PDAC cell-derived extracellular S100A4 promotes LAMB3 expression in PSCs. S100A4 depletion significantly reduced histological tumor aggressiveness in a pancreatic tumor orthotopic model and inhibited metastasis. To explore the therapeutic potential of these findings, we developed de novo S100A4-targeting inhibitory peptides using AI-guided structure modeling and confirmed their inhibitory effects on collective invasion. Collectively, our findings identify S100A4 as a critical driver of collective invasion and PDAC metastasis and support extracellular S100A4 as a potential target for AI-guided therapeutic intervention.</p>

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S100A4 promotes collective invasion of pancreatic ductal adenocarcinoma and its blockade suppresses metastasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Dong Woo Son,
  • Ye-jin Lim,
  • Chae Won Yu,
  • Min Jung Cha,
  • Eun Ji Lee,
  • Hyori Kim,
  • Heechan Lee,
  • Seung Mo Hong,
  • Hahnbeom Park,
  • Suhwan Chang

摘要

Most solid tumors invade peritumoral tissues as multicellular units while maintaining cell-cell interactions and epithelial characteristics, a process known as collective invasion. Our previous proteomic analysis revealed that S100-family proteins were upregulated in the PDAC secretome. Therefore, we aimed to elucidate the functional roles of these proteins in collective invasion and PDAC metastasis. To this end, we established a 3D collective invasion model using co-culture spheroids composed of PDAC cells and pancreatic stellate cells (PSCs). Using this model, we found that S100A4 contributes to collective invasion by mediating PDAC cell-PSC interactions, with S100A4 knockdown inhibiting collective invasion and S100A4 overexpression promoting it. Additionally, depletion of S100A in PDAC cells reduced trans-endothelial migration and cancer cell adhesion to endothelial cells. Mechanistically, PDAC cell-derived extracellular S100A4 promotes LAMB3 expression in PSCs. S100A4 depletion significantly reduced histological tumor aggressiveness in a pancreatic tumor orthotopic model and inhibited metastasis. To explore the therapeutic potential of these findings, we developed de novo S100A4-targeting inhibitory peptides using AI-guided structure modeling and confirmed their inhibitory effects on collective invasion. Collectively, our findings identify S100A4 as a critical driver of collective invasion and PDAC metastasis and support extracellular S100A4 as a potential target for AI-guided therapeutic intervention.