Epithelial cell dynasties: competition dynamics in homeostasis and precancer

 

 

Studying the proliferative organization and self-renewal capacity of healthy normal tissues is paramount to understand adult tissue homeostasis as well as to address mutant clone expansion during cancer initiation. Yet, the mechanisms by which tissues orchestrate cell fate commitment to achieve an adequate balance between cell proliferation and cellular loss have remained largely unknown until recent years. By combining quantitative lineage tracing in transgenic mouse models and mathematical modeling we have achieved a great progress in cell kinetic characterizations in vivo. In this talk I will describe our discoveries in the context of the fast-renewing epithelia of the esophagus and the skin epidermis, where we have shown that cell renewal is maintained by a single population of progenitor cells undergoing stochastic fates. This paradigm has allowed us to infer important constraints on mutant clone growth that might explain the surprising reluctance of these tissues to form tumors in mouse upon mutagen treatment. Then, I will move to explain our current efforts and challenges to address cellular dynamics in slow-renewing epithelia, and more in particular the bladder urothelium, a paradoxical case of a tissue with one of the lowest proliferation rates but source of a highly prevalent type of cancer that typically occurs with multifocality.