Axl regulates stem cell traits in normal and malignant epithelial cells: Basic biology and clinical translation

In spite of recent advances in new therapeutics, cancer remains a leading cause of death. A confounding reality for anti-cancer treatment is the remarkable cellular diversity within tumors. Hence, delineating the mechanisms underlying how a tumor achieves this phenotypic diversity, and how this contributes to current treatment failures, is a major health issue. Malignant cells activate gene programs in response to drug treatment and host immune challenge that engender cellular plasticity programs characteristic of normal stem cells. We demonstrated that the Axl receptor tyrosine kinase associated with malignant breast carcinomas. Remarkably, we revealed that Axl is expressed by normal adult mammary epithelial stem cells. Axl signaling contributes to the maintenance of the normal epithelial hierarchy required for breast tissue homeostasis. Hence, Axl signaling represents a unique link between stem cell traits in both normal and malignant epithelial cells. We are exploring how Axl is activated in malignant cells and how this contributes to therapy resistance. The current clinical development of an Axl inhibitor will provide a unique opportunity to rapidly translate the results from this project into clinical benefit for cancer patients.

In spite of recent advances in the development of molecularly targeted therapeutics, cancer remains a leading cause of death. A confounding reality for anti-cancer treatment is the cellular heterogeneity of tumors. Hence, delineating the mechanisms underlying how a tumor evolves from it's clonal origin to achieve this phenotypic diversity, and how this contributes to current treatment failures, is a major health issue. Malignant cells activate gene programs in response to drug treatment and host immune challenge that engender cellular plasticity programs. In particular, the acquisition of stem cell-like traits is strongly correlated with tumor heterogeneity, drug resistance and poor clinical outcome. Through a previous FRIMEDPRO grant (Project ID: 204868) we demonstrated that the Axl receptor tyrosine kinase is required for malignant and stem-cell traits of breast carcinomas. Remarkably, we discovered that Axl is expressed by normal adult mammary epithelial stem cells. Axl signaling contributes to the maintenance of stem cells within the normal epithelial hierarchy required for tissue homeostasis. Hence, Axl signaling represents a unique link between stem cell traits in both normal and malignant epithelial cells. We propose to apply a comprehensive, comparative approach to: i) elucidate the microenvironmental determinants of Axl expression; and ii) map the Axl signal transduction network, in both normal adult epithelial stem and carcinoma cells. Our experimental approach comprises an innovative integration of quantitative screening methodologies (MEArray, mass cytometry) to measure Axl-dependent regulation of plasticity gene programming.This will provide novel insight into the tumor heterogeneity and drug resistance mechanisms of malignant carcinomas. The current clinical development of an Axl inhibitor will provide a unique opportunity to rapidly translate the results from this project into clinical benefit for cancer patients.