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Genetically Defined Organoid Models Reveal Mechanisms Driving Squamous Cell Neoplastic Evolution and Identify

Hua Zhao1, Young Min Park2, Yueyuan Zheng3

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Understanding early upper aerodigestive squamous cell carcinoma (UASCC) is crucial. Genetically defined organoid models reveal a diminished senescence program, regulated by ANXA1, that suppresses early cancer development.

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Area of Science:

  • Oncology
  • Cancer Biology
  • Molecular Pathology

Background:

  • Upper aerodigestive squamous cell carcinoma (UASCC) is a lethal cancer with poorly understood early development.
  • Genetic mutations play a key role in neoplastic transformation.

Purpose of the Study:

  • To investigate the early mechanisms of UASCC development using genetically defined organoid models.
  • To identify key pathways and potential therapeutic targets in early-stage UASCC.

Main Methods:

  • Generation and characterization of over 25 genetically-defined murine and human oral/esophageal organoid models.
  • Utilizing single-cell analysis to study cellular changes during malignant transformation.
  • Performing high-throughput drug screening on organoid models.

Main Results:

  • TP53 and CDKN2A double knockout induced dysplasia, hyperproliferation, and loss of differentiation, exacerbated by other driver mutations.
  • Single-cell analysis showed expansion of basal and proliferative cells, with a loss of differentiated cells.
  • A senescence program regulated by ANXA1 was diminished in early neoplastic evolution.
  • The ANXA1-SMAD3-p27KIP1 pathway was identified as a critical regulator of senescence.
  • PIK3CA-driven organoids showed sensitivity to Mitomycin C and Onalespib.

Conclusions:

  • Genetically-defined organoid models are valuable for studying early cancer biology.
  • The ANXA1-SMAD3-p27KIP1 pathway is a critical suppressor of neoplastic features in early UASCC.
  • Targeted therapies may be effective against specific genetic drivers in UASCC.