The two major focuses of the lab are:
1. Oncogenic kinase fusions and signaling from RTK protein granules
Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS/MAPK signaling cascade was thought to occur exclusively from lipid membrane compartments in mammalian cells and cancer. Chimeric (fusion) oncoproteins involving RTKs such as anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) represent prominent drivers of oncogenic RTK/RAS/MAPK signaling across many cancer subtypes. We recently discovered that notable RTK fusion oncoproteins including EML4-ALK and CCDC6-RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that coordinate lipid-membrane independent RAS activation and MAPK signaling. These data establish a new pathogenic subcellular structure in cancer: membraneless RTK protein granules. Ongoing work in the laboratory aims to build a detailed molecular understanding of the signaling properties of these biomolecular condensates and test whether pharmacologic disruption of RTK protein granules can be translated into a new therapeutic strategy for this class of cancers.
2. Oncogene disruption of cellular DNA repair networks
The DNA damage response (DDR) is a tightly regulated network with built-in redundancies and layers of control. Loss of specific DDR pathways drives oncogenesis in certain cancers (e.g., BRCA mutations), but whether oncogenes, in general, create tumor-specific vulnerabilities within DDR networks is unknown. The need for mechanistic inquiry into oncogene-induced dependencies is particularly acute for the diverse set of transcription factor (TF) fusion-driven cancers, as the oncoproteins have proven intractable drug targets due to the difficulty of direct pharmacologic inhibition. Our work focuses on the FET family of RNA-binding proteins (FUS, EWS, TAF15) that are frequent 5′ oncogenic TF fusion partners in a diversity of pediatric sarcomas and leukemias. FET family members are among the earliest proteins recruited to DNA double-strand breaks (DSBs), though the functional role of both native FET proteins and FET oncogenic fusions in DSB repair remains poorly defined. Our work on the pediatric bone tumor Ewing sarcoma has uncovered a functional defect in the DDR caused by the EWS-FLI1 fusion oncoprotein, and ongoing studies aim to characterize the mechanisms by which EWS-FLI1 disrupts DNA repair and exploit this vulnerability through novel therapeutics.