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Pan-cancer N-glycoproteomic atlas of patient-derived xenografts uncovers FAT2 as an actionable surface target

Meinusha Govindarajan1, Salvador Mejia-Guerrero2, Shawn C Chafe3

  • 1Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada.

Cell Reports. Medicine
|January 24, 2026
PubMed

Insights

Researchers identified FAT2 as a promising cancer target using N-glycoproteomics on patient-derived xenografts. FAT2-targeted therapies, including CAR-T cells, show anti-tumor activity, especially in squamous cell cancers.

Area of Science:

  • Oncology
  • Proteomics
  • Immunotherapy

Background:

  • Cell surface proteins are crucial for cancer signaling and therapeutic targeting.
  • Profiling cell surface proteins is challenging, limiting therapeutic development.
  • Patient-derived xenografts (PDXs) offer a valuable model for cancer research.

Purpose of the Study:

  • To create a pan-cancer atlas of cancer-derived surface proteins using N-glycoproteomics.
  • To develop a pipeline for identifying immunotherapeutic targets from surface protein profiles.
  • To validate FAT2 as a potential therapeutic target for squamous cell cancers.

Main Methods:

  • N-glycoproteomics analysis of 85 patient-derived xenografts (PDXs).
  • Development of a target discovery pipeline for prioritizing surface proteins.
  • Functional studies on FAT2 in head and neck squamous cell cancer (HNSC) models.
  • Evaluation of Chimeric Antigen Receptor (CAR)-T cell therapy targeting FAT2.

Main Results:

  • Glyco PDXplorer, an in vivo atlas of cancer-derived surface proteins, was constructed.
  • FAT2 was identified as a squamous-cancer-enriched surface protein with minimal expression in normal tissues.
  • FAT2 is essential for HNSC cell growth and adhesion via surface architecture and integrin-PI3K signaling.
  • FAT2-targeted CAR-T cells demonstrated significant anti-tumor activity.

Conclusions:

  • FAT2 is a validated therapeutic target for squamous cell cancers.
  • The Glyco PDXplorer platform facilitates discovery of novel cancer targets.
  • This work establishes a foundation for FAT2-targeted therapies and broader immunotherapeutic strategies.
Keywords:
CAR-TFAT2N-glycoproteomicshead and neck squamous cancerimmunotherapypan-cancer atlaspatient-derived xenograftssquamous cell cancersurfaceometargeted therapy

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