Unmasking in vivo cell dynamics in mammary tissue and mammary tumours
- Abstract number
- 211
- Corresponding Email
- [email protected]
- Session
- Stream 5: Imaging in Development and Disease
- Authors
- Colinda Scheele (2), Hendrik Messal (1), Stefan Hutten (1), Jos Jonkers (1), Benjamin Simons (3), Jacco van Rheenen (1)
- Affiliations
-
1. Netherlands Cancer Institute
2. VIB- KU Leuven Center for Cancer Biology
3. Wellcome Trust/Cancer Research UK Gurdon Institute
- Keywords
whole-mount imaging, 3D microscopy, intravital microscopy, Field cancerization, mammary gland, clonal dynamics, lineage tracing
- Abstract text
Cells that have acquired mutations in oncogenic driver genes are abundantly present in healthy tissues, but they rarely develop into tumors. Yet, the underlying protection mechanisms that prevent tumor formation are largely unknown. To resolve these mechanisms in breast tissue, and to understand how they may be overcome by mutant cells to drive field cancerization, we combined whole-organ 3D imaging and intravital microscopy of the mammary gland with genetic lineage tracing and biophysical modelling. We followed the behavior of oncogenic cells (Brca1-/-;Trp53-/-), and compared these dynamics with the behavior of cells bearing neutral mutations in the mouse mammary gland epithelium. From the quantitative image analysis of the clonal dynamics in normal tissue, we found that the ductal epithelial network is supported by a short, lineage-restricted, stem-progenitor cell hierarchy. This hierarchy confers a first protection mechanism against field cancerization and subsequent tumor formation in the mammary gland, as only clones initiated in the stem cell compartment are able to survive. At longer times, local tissue remodeling driven by 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. Eventually, this “inflationary” process of geometric 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.