Clonal Dynamics and Hierarchical Organization Mediate Tumor Initiation

Cells that have accumulated oncogenic alterations are thought to exhibit a clonal advantage over adjacent normal cells during tumor initiation and progression. However, it is unclear whether stem cells (SC) and progenitor cells exhibit similar abilities to drive tumor initiation in response to oncogenic activation. To determine whether the location and identity of the cell of origin confers a competitive clonal advantage in basal cell carcinoma (BCC) initiation, Sanchez-Danes, Hannezo, and colleagues expressed oncogenic mouse smoothened homolog gene (SmoM2) in mouse epidermal stem cells and committed progenitors (CP) to activate hedgehog (Hh) signaling. Expression of SmoM2 in SCs resulted in BCC initiation, but expression of SmoM2 in CPs resulted in the formation of preneoplastic lesions that did not progress to BCC. Further, SmoM2 expression in the two different lineage compartments of tail epidermis, scale and interscale, revealed that BCCs arose from only interscale cells after oncogenic activation. Lineage tracing identified a hierarchical organization of SCs and CPs in the interscale compartment and showed that only CPs maintained the scale compartment. Consistent with these findings, only interscale SCs gave rise to BCCs upon SmoM2 activation. Oncogenic activation enhanced the bias of SCs toward self-renewal and subsequently proliferation but did not decrease the bias of CPs toward differentiation, which resulted in increased proliferation and clonal persistence of SCs compared to CPs. Expression of p53 was higher in CPs compared to SCs, and deletion of p53 in interscale SmoM2-targeted CPs resulted in increased proliferation and BCC formation, suggesting that p53 restricted CP-mediated BCC initiation. Mechanistically, p53 induced apoptosis and cell-cycle arrest in SmoM2-targeted CPs. Taken together, these findings show that the clonal expansion of cells harboring oncogenic alterations is dependent upon the growth, survival, and clonal dynamics of the tumor cell of origin.

Sánchez-Danés A, Hannezo E, Larsimont JC, Liagre M, Youssef KK, Simons BD, et al. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 2016 Jul 8 [Epub ahead of print].