Integrin α3β1 in hair bulge stem cells modulates CCN2 expression and promotes skin tumorigenesis

Area of Science:

• Dermatology
• Cancer Biology
• Stem Cell Biology

Background:

• Integrin α3β1 is crucial in epidermal homeostasis and wound healing.
• Hair bulge (HB) stem cells (SCs) were previously thought to be the origin of skin tumors in the 7,12-Dimethylbenz[]anthracene/12--tetradecanoylphorbol-13-acetate (DMBA/TPA) model.
• The role of HB SCs and integrin α3β1 in skin carcinogenesis requires further elucidation.

Purpose of the Study:

• To investigate the role of integrin α3β1 in epidermal stem cells during skin carcinogenesis.
• To determine the contribution of hair bulge stem cells to tumor formation in the DMBA/TPA model.
• To identify molecular mechanisms by which integrin α3β1 influences skin tumorigenesis.

Main Methods:

• Utilized a reporter mouse line with inducible deletion of integrin α3β1 in hair bulge stem cells.
• Performed 7,12-Dimethylbenz[]anthracene/12--tetradecanoylphorbol-13-acetate (DMBA/TPA) two-stage skin carcinogenesis.
• Conducted RNA sequencing on isolated hair bulge stem cells and in vitro assays with transformed keratinocytes.

Main Results:

• Epidermal-specific deletion of integrin α3β1 significantly reduced papilloma formation.
• Hair bulge stem cells remained in their niche and were largely absent from tumors, challenging previous assumptions.
• Integrin α3β1-dependent expression of connective tissue growth factor (CCN2) was observed, promoting transformed keratinocyte growth.

Conclusions:

• Hair bulge stem cells contribute to skin tumorigenesis in an integrin α3β1-dependent manner.
• Integrin α3β1 signaling in HB SCs modulates CCN2 secretion, creating a permissive environment for tumor growth.
• Findings suggest a novel role for HB SCs in skin cancer beyond being direct cancer cells-of-origin.