Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium.
Elife
; 102021 01 04.
Article
en En
| MEDLINE
| ID: mdl-33393458
ABSTRACT
Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced HrasG12V in single murine epidermal cells and followed them long term. We observed that HrasG12V promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intraclonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of HrasG12V-driven differentiation, we screened known Ras-effector in vivo and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Adaptadoras Transductoras de Señales
/
Células Epiteliales
/
Proteínas Reguladoras de la Apoptosis
/
Carcinogénesis
/
Células Epidérmicas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Elife
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos