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Targeted Expression of GFP in the Hair Follicle Using Ex Vivo Viral Transduction
Published on: March 17, 2008
Hair follicle regeneration suppresses Ras-driven oncogenic growth
Cristiana M Pineda1, David G Gonzalez1, Catherine Matte-Martone1
1Department of Genetics, Yale School of Medicine, New Haven, CT.
Abstract:
Mutations associated with tumor development in certain tissues can be nontumorigenic in others, yet the mechanisms underlying these different outcomes remains poorly understood. To address this, we targeted an activating Hras mutation to hair follicle stem cells and discovered that Hras mutant cells outcompete wild-type neighbors yet are integrated into clinically normal skin hair follicles. In contrast, targeting the Hras mutation to the upper noncycling region of the skin epithelium leads to benign outgrowths. Follicular Hras mutant cells autonomously and nonautonomously enhance regeneration, which directs mutant cells into continuous tissue cycling to promote integration rather than aberrancy. This follicular tolerance is maintained under additional challenges that promote tumorigenesis in the epidermis, including aging, injury, and a secondary mutation. Thus, the hair follicle possesses a unique, enhanced capacity to integrate and contain Hras mutant cells within both homeostatic and perturbed tissue, demonstrating that in the skin, multiple, distinct mechanisms exist to suppress oncogenic growth.
Insights
Oncogenic mutations behave differently across tissues. The hair follicle integrates Hras mutant cells, preventing tumor formation unlike the epidermis, revealing tissue-specific cancer suppression mechanisms.
Area of Science:
- Oncology
- Dermatology
- Stem Cell Biology
Background:
- Activating mutations in Hras are linked to tumor development.
- The tissue microenvironment influences the oncogenic potential of mutations.
- Mechanisms of tissue-specific tumor suppression are not fully understood.
Purpose of the Study:
- To investigate why Hras mutations cause tumors in some tissues but not others.
- To explore the role of the hair follicle in suppressing oncogenic Hras.
- To understand the mechanisms of tissue tolerance to oncogenic mutations.
Main Methods:
- Targeting an activating Hras mutation to hair follicle stem cells and skin epithelium in vivo.
- Assessing the integration and proliferation of mutant cells.
- Evaluating tissue regeneration and cycling dynamics.
- Challenging the system with factors promoting tumorigenesis (aging, injury, secondary mutations).
Main Results:
- Hras mutant cells were integrated into normal skin hair follicles, outcompeting wild-type cells.
- Hras mutations in the upper skin epithelium led to benign outgrowths.
- Follicular Hras mutant cells enhanced regeneration, promoting integration into cycling tissue.
- The hair follicle maintained tolerance to Hras mutations even under conditions promoting epidermal tumorigenesis.
Conclusions:
- The hair follicle has a unique capacity to integrate and contain Hras mutant cells.
- Distinct tissue-specific mechanisms exist in the skin to suppress oncogenic growth.
- Understanding these mechanisms could inform cancer prevention and therapy strategies.
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