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Exploiting the origins of Ras mediated squamous cell carcinoma to develop novel therapeutic interventions

Andrew C White1, William E Lowry

  • 1Department of Molecular, Cell and Developmental Biology; Jonsson Comprehensive Cancer Center; Eli and Edythe Broad Center for Stem Cell Research; Molecular Biology Institute; University of California, Los Angeles; Los Angeles, CA USA.

Small Gtpases
|May 1, 2012
PubMed

Insights

Ras activation drives squamous cell carcinoma (SCC) initiation from hair follicle stem cells (HFSCs). Understanding these mechanisms may lead to novel cancer therapeutics targeting Ras-driven tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • The small GTPase Ras is frequently activated in human cancers, but clinical blockade of Ras activity has been largely ineffective.
  • Squamous cell carcinoma (SCC) is a common cancer where Ras pathway dysregulation plays a significant role.

Purpose of the Study:

  • To investigate the cell of origin for Ras-driven SCC using an inducible mouse model.
  • To elucidate the molecular mechanisms underlying Ras-mediated tumorigenesis in the epidermis.
  • To identify context-dependent activities of Ras in cancer initiation.

Main Methods:

  • Utilized an inducible mouse model to study the effects of Ras activation in vivo.
  • Analyzed the role of hair follicle stem cells (HFSCs) and their progeny in SCC development.
  • Investigated the differential sensitivity of epidermal cells to Ras activation.

Main Results:

  • Hair follicle stem cells (HFSCs) were identified as the cell of origin for SCC.
  • More restricted progeny of HFSCs were refractory to Ras activation and could not serve as cancer cells of origin.
  • Demonstrated differential sensitivities of epidermal cells to Ras-mediated oncogenesis.

Conclusions:

  • HFSCs are the critical cell type for initiating Ras-driven SCC.
  • Targeting specific molecular mechanisms in HFSCs could lead to novel SCC therapeutics.
  • Exploiting differential cellular sensitivities to Ras activation offers a promising therapeutic strategy for SCC.

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