We aim to understand how the balance between tissue growth and regression is maintained and what goes awry during cancer. To begin to address how tumor growth is regulated, my lab combined genetic approaches with live imaging to investigate the role of an evolutionary conserved pathway, Wnt/ β-catenin, during tissue growth. These efforts uncovered a novel mechanism of action for β-catenin that acts non-cell autonomously within the hair follicle stem cells by recruiting wild-type cells to induce de novo hair growths that ultimately result in tumors. Additionally, we show that β-catenin driven growth can form and expand in absence of the mesenchymal niche (Deschene*, Myung*, Science 2014; Figure and movie).
To start to understand how tumor regression can be regulated, 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. We demonstrate that the employed differentiation cues, retinoic acid, when used on SCC induce the regression of these malignant tumors (Zito, Nature communication 2014; Figure).
This work changes our understanding of how cells that carry mutation can interact with neighboring cells expanding our understanding of how tumor progression and regression is regulated. While these above models have allowed us to understand novel principles of tumoral growth and regression, whether a cell's position within a tissue influences different tumoral outcomes, and the early cell behaviors that are adopted by stem and other cell types that lead to malignancy are still unclear. Cancer is thought to derive from relatively few mutated cells. Current approaches to investigate cancer utilize the broad induction of specific mutations in the large majority of cells within a given tissue. Thus we have developed approaches that allow us to interrogate how normal tissue interfaces with mutated cells in live mice. We are in particular interested in mutations associated with SCC such as clones bearing Hras mutations in combination with a loss of TGFβ function. Thus, we are studying the dynamics between mutant clones (double- and single-mutant) and wild-type neighboring tissues to begin to elucidate the set of behaviors and interactions that take place. Additionally, we aim to set up a map of interactions with the niche to understand the molecular underpinnings of these interactions. Functional investigation of both oncogenic signaling pathways and different cellular interactions will help us elucidate the critical set of decisions that lead to cancer.