Developing tissues enacts complex local growth control signals that instruct the final pattern and size of mature organs. Perturbations of these signals cause a wide spectrum of developmental disorders, including congenital heart diseases. Further, oncogenic activation of the EGFR-RAS pathway overrides these growth control signals post-developmentally to give rise to fast growing tumors that are resistant to anti-cancer drugs. Thus, understanding the molecular basis of tissue growth control has the potential to expose vulnerabilities that can be targeted therapeutically to improve the management of developmental diseases and to achieve the re-sensitization of EGFR-RAS cancers to existing therapies.

Using the developing Drosophila wing as a model we are uncovering novel regulators of organ size control, including JIP3 and ARF6. ARF6 promotes Hedgehog signaling which is required for patterning and Hippo-mediated tissue growth. JIP3 acts downstream of Hippo by regulating the inhibitor of apoptosis molecule Diap1, thereby controlling final wing size. Also, by integrating Drosophila, human tissue culture, clinical samples, and mouse models of EGFR-RAS tumors, we are illuminating emergent tumor-host signaling interactions that enable EGFR-RAS tumors to acquire resistance against radiotherapy, genotoxic chemotherapies, and targeted therapies.