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Updated: Mar 15, 2026

Cell Population Analyses During Skin Carcinogenesis
06:53

Cell Population Analyses During Skin Carcinogenesis

Published on: August 21, 2013

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Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma

Patrizia Cammareri1, Aidan M Rose2, David F Vincent1

  • 1Wnt Signaling and Colorectal Cancer Group, Cancer Research UK Beatson Institute, Institute of Cancer Sciences, Glasgow University, Garscube Estate, Switichback Road, Glasgow G61 1BD, UK.

Nature Communications
|August 26, 2016
PubMed

Insights

Oncogenic BRAF inhibitor treatment can cause skin cancer (cSCC) due to pathway activation. Mutations in TGFBR1/2 and loss of TGFβ signaling in stem cells drive cSCC development, indicating these stem cells are key to skin tumorigenesis.

Area of Science:

  • Dermatology
  • Oncology
  • Molecular Biology

Background:

  • Melanoma patients on BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC).
  • This is driven by paradoxical RAS/RAF/MAPK pathway activation.
  • TGFβ signaling plays a role in skin homeostasis.

Purpose of the Study:

  • To identify genetic drivers of vemurafenib-induced cSCC.
  • To investigate the role of TGFβ signaling in skin stem cells in cSCC development.
  • To explore the cell of origin for cSCC.

Main Methods:

  • Analysis of human vemurafenib-induced skin lesions and sporadic cSCC for mutations.
  • Functional studies of TGFβ signaling in mouse models.
  • Genetic manipulation of stem cells (LGR5+ve) in mice.

Main Results:

  • Frequent TGFBR1 and TGFBR2 mutations were found in human cSCC lesions.
  • These mutations ablate canonical TGFβ Smad signaling.
  • Combined MAPK hyperactivation or Tp53 mutation with TGFβ signaling loss in LGR5+ve stem cells rapidly induced cSCC in mice.

Conclusions:

  • LGR5+ve stem cells are identified as potential cells of origin for cSCC.
  • Aberrant RAS/RAF/MAPK pathway activation or Tp53 mutation, alongside TGFβ signaling loss, are critical events in skin tumorigenesis.

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