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<p>Mucoepidermoid carcinoma (MEC) is the most frequently occurring salivary gland malignancy. Here, we investigated transcriptomic profiles of human fetal and adult salivary glands and MEC tumors to assess programs involved in MEC progression. Molecular and genetic analyses revealed that MEC tumors and fetal salivary glands share proliferative and developmental gene expression profiles that implicate an FGFR-p53 signaling axis in salivary MEC progression. Based on these findings, we developed a genetically engineered mouse model of advanced MEC via targeted expression of the CRTC1-MAML2 oncogene in salivary ductal cells. Specifically, CRTC1-MAML2 expression combined with p53 dysregulation in salivary ducts rewires FGF signaling to drive formation of tumors with histological and molecular features of high-grade MEC. The combined bioinformatics and mouse modeling of this study demonstrate that salivary MEC progression is underpinned by reactivation of developmental signaling programs and suggests a role for FGFR targeted therapies in the treatment of high-grade MEC.</p><p></p>

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An FGFR-p53 developmental signaling axis drives salivary cancer progression

  • 期刊论文

  • 发表日期：

    2025年6月2日

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  • Adele M. Musicant,
  • Julia M. R. Billington,
  • Jeffrey S. Damrauer,
  • Jennifer L. Modliszewski,
  • Luane J. B. Landau,
  • Yi-Hsuan Tsai,
  • Jay H. Mehta,
  • John Powers,
  • Renee Betancourt,
  • Radhika Sekhri,
  • Ricardo J. Padilla,
  • Juan C. Hernandez-Prera,
  • D. Neil Hayes,
  • Trevor G. Hackman,
  • Omer Gokcumen,
  • Sarah M. Knox,
  • Antonio L. Amelio

摘要

Mucoepidermoid carcinoma (MEC) is the most frequently occurring salivary gland malignancy. Here, we investigated transcriptomic profiles of human fetal and adult salivary glands and MEC tumors to assess programs involved in MEC progression. Molecular and genetic analyses revealed that MEC tumors and fetal salivary glands share proliferative and developmental gene expression profiles that implicate an FGFR-p53 signaling axis in salivary MEC progression. Based on these findings, we developed a genetically engineered mouse model of advanced MEC via targeted expression of the CRTC1-MAML2 oncogene in salivary ductal cells. Specifically, CRTC1-MAML2 expression combined with p53 dysregulation in salivary ducts rewires FGF signaling to drive formation of tumors with histological and molecular features of high-grade MEC. The combined bioinformatics and mouse modeling of this study demonstrate that salivary MEC progression is underpinned by reactivation of developmental signaling programs and suggests a role for FGFR targeted therapies in the treatment of high-grade MEC.