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RAS-mediated suppression of PAR3 and its effects on SCC initiation and tissue architecture occur independently of

Ji Ling1, Maria Sckaff1, Manisha Tiwari1

  • 1Department of Dermatology, Department of Cellular and Molecular Medicine, UCSD Stem Cell Program, University of California, San Diego, La Jolla, CA 92093-0869, USA.

Journal of Cell Science
|November 11, 2020
PubMed

Insights

RAS-dependent suppression of PAR3 accelerates squamous cell carcinoma (SCC) development by disrupting cell adhesion and division. MAPK pathway inhibition restored normal tissue architecture, identifying PAR3 as a key regulator in early SCC.

Area of Science:

  • Oncology
  • Cell Biology
  • Developmental Biology

Background:

  • Epithelial homeostasis relies on controlled cell division, influenced by polarity factors and spatial cues.
  • Investigating spindle orientation in human epithelial carcinoma has been limited by the absence of suitable skin models.

Purpose of the Study:

  • To investigate spindle orientation deregulation in human squamous cell carcinoma (SCC) using an inducible model.
  • To identify molecular mechanisms driving early epithelial disorganization in SCC.

Main Methods:

  • Development of an inducible human squamous cell carcinoma (SCC) model.
  • Analysis of PAR3 (PARD3) expression and its role in cell adhesion and spindle orientation.
  • Pharmacological inhibition of the MAPK pathway.

Main Results:

  • RAS-dependent suppression of PAR3 accelerates epithelial disorganization in early SCC.
  • Reduced PAR3 expression leads to loss of E-cadherin-mediated cell adhesion and misoriented cell division.
  • MAPK pathway inhibition reverses PAR3 suppression, adhesion defects, and spindle misorientation.

Conclusions:

  • PAR3 is a critical regulator of tissue architecture during initial human SCC development.
  • Temporal analysis of human neoplasia is a powerful approach for studying early oncogenesis.
  • Targeting the RAS-MAPK-PAR3 axis may offer therapeutic strategies for SCC.
Keywords:
Cell adhesionCell junctionEpidermisEpithelial organizationMitotic spindle orientationPolaritySkinTumorigenesis

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