Cell type-specific morphogen induction resulting from Ras oncogene expression.

Morphogens are growth factor-like substances that perform developmental functions by context-specific expression that drives organogenesis and tissue growth in a gradient fashion. Two common morphogen signaling pathways are the bone morphogenetic protein (BMP) pathway and the Wnt signaling pathway. To describe in a succinct manner the most relevant morphogens functioning in human cells during transformation driven by an oncogene, we measured total expression in human epithelial cells of the lung following expression of wild-type KRas or oncogenic KRas G12V. Human cells produced BMP4, BMP7 and BMP2 and silenced BMP6 in response to KRas oncogene growth signaling that simultaneously resulted in induction of senescence. In response to KRas G12V, cells instead silenced BMP4, activated BMP6, and produced BMP8A and BMP8B. Cells expressing wild-type KRas produced soluble Wnt ligands Wnt3a, Wnt9a, Wnt10a and Wnt4 in greatest quantity, while silencing Wnt3. In contrast, cells expressing KRas G12V silenced or repressed Wnt10a, Wnt4 and Wnt3, while activating Wnt5b and Wnt5a. Additionally, while cells expressing KRas G12V produced modest quantities of Wnt7a, it was repressed in cells expressing wild-type KRas. Wnt5a and Wnt5b, together with BMP8a and BMP8b appear to possess morphogen function with highest transformation potential.