Deep sequencing of aged yet phenotypically normal human skin, blood and esophagus has revealed that tissues are a mosaic of mutated cells. Yet it remains unclear how normal tissues cope with the presence of mutant cells, and what goes awry during cancer.
Using our powerful live imaging approach, we demonstrated that inducing the activating mutation of a critical regulator of growth, Wnt/β-catenin, heterogeneous tumors made up of both mutant β-catenin cells and wild-type cells formed, revealing a dynamic interaction between mutant and wild-type cells. (Deschene*, Myung*, 2014). When we examined how these mutant populations affect the long-term fate of the tissue, we discovered that skin epithelium can correct minor and major perturbations to skin architecture induced by an activating mutation of a critical regulator of growth, Wnt/β-catenin (Figure 1). This tissue correction is an active process that requires the action of wild-type cells. We have also found that the ability to resolve normal tissue architecture and return to homeostasis is conserved across different mutations such as oncogenic HRas as well as in situations of non-mutational insult (Brown*, Pineda*, 2017).
To gain insight into what goes awry during cancer, we took advantage of two contrasting mouse cancer models: a unique benign skin tumor that regresses spontaneously, keratoacanthoma, as well as a malignant skin tumor, Squamous Cell Carcinoma (SCC). We demonstrated that self-regressing keratoacanthoma tumors counterbalance excessive proliferation by employing a homeostatic mechanism of differentiation to regress (Figure 2). Furthermore, we demonstrate such differentiation cues as retinoic acid, can induce the regression of malignant SCC tumors (Zito, 2014). This work further ellucidates our understanding of the interactions between mutant cells and their neighbors.
Moving forward, we are determined to understand the combination of factors that allow a tissue to integrate, tolerate and/or eliminate cells carrying different mutations while maintaining a homeostatic steady state, as well as capture the critical cellular behaviors and molecular cross-talk occurring within and between mutant and wild-type populations that drive cancer emergence.