Cells that have acquired mutations in driver genes are abundant in tissues of healthy individuals. In breast tissue it has been suggested that large fields of the epithelial tree can carry mutations leading to a “sick lobe”. These mutant fields may predispose to tumor formation, but in most cases mutant branches stay morphologically untransformed. The underlying mechanisms that on the one hand allow these mutant cells to stay under the radar, and on the other hand prevent cancerous cells from transformation are largely unknown. In clinical samples of non-invasive breast cancer, we combined high-resolution 3D tissue reconstruction with copy number variation sequencing and confirmed the presence of cells with oncogenic mutations in morphologically normal breast ducts, indicating that field cancerization may precede tumor formation. Using lineage tracing of mutant cells combined with intravital and whole-tissue imaging in murine mammary glands allowed us to map the dynamics by which mutant fields arise. Strikingly, in most cases, these cancerous fields did not transform the tissue. By combining quantitative modelling with 3D imaging over time, we found three mechanisms that protect the mammary epithelium from transformation: 1. Tissue hierarchy confers the first protection mechanism against field cancerization as only clones initiated in the stem cell compartment survive over the short-term. 2. At longer times, local tissue remodeling during the estrous cycle leads to stochastic collective stem cell amplification and loss. This process provides a second mechanism of protection, leading to the elimination of the majority of mutant clones, while massively accelerating the expansion of a minority of clones that, by chance, survive. 3. Eventually, this process of clone expansion becomes restrained by the one-dimensional geometry of the ducts, providing a third mechanism to protect the epithelium against uncontrolled colonization by mutant clones. Together, these findings reveal layers of protection that serve to eliminate the majority of cells that acquire chance somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas leading to field cancerization.
(This seminar will take place in person and online)