The Vasudevan Lab studies growth factor signaling during development and cancer with an emphasis on neurofibromatosis with the end goal of developing novel diagnostic and therapeutic strategies.
Ongoing projects in the lab include:
Neurofibromatosis:
1. Understanding the mediators of neurofibromatosis tumor suppressor function
2. Elucidating therapeutic vulnerabilities in neurofibromatosis associated cancers
3. Delineating mechanisms of tumor and normal tissue heterogeneity in people with neurofibromatosis
Cancer genomics
1. Defining molecular groups and biomarkers of peripheral nerve tumors
2. Determining the molecular classification of NF1 mutant tumors
3. Uncovering clinical subgroups of brain metastases
Growth factor signaling
1. Dissecting Ras GAP specificity in development and disease
2. Linking how receptor tyrosine kinase activation mediates downstream cellular outputs
Neurofibromatosis: The cancer predisposition syndrome neurofibromatosis type I (NF1) is caused by loss of the neurofibromin tumor suppressor gene, a GAP that negatively regulates Ras signaling and serves as a key downstream effector of RTKs. Patients with NF1 are at increased risk for developing many nervous system tumors, including Schwann cell derived neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). To personalize treatment for these patients, we have defined predictive and prognostic signatures in MPNSTs. Our more recent work focuses on how Schwann cell differentiation underlies malignant transformation and treatment resistance to MEK inhibitors, the only FDA approved therapy for neurofibromas arising in patients with NF1, identifying a functional relationship between the NF1 and NF2 tumor suppressors.
Cancer genomics: Understanding the molecular correlates of tumorigenesis requires integration of multiple bulk and single cell genomic modalities including DNA methylation profiling, whole exome sequencing (WES), and RNA-sequencing (RNA-seq). We have previously applied such an integrative approach to meningiomas, the most common primary CNS tumor in the United States, and ependymoma, both of which are associated with neurofibromatosis, and to melanoma brain metastasis, which are the most common cause of death in patients with melanoma.
Growth factor signal specficificity through receptor tyrosine kinases (RTKs) and Ras GAP proteins: The mechanisms through which receptor tyrosine kinases specify distinct cellular outcomes despite signaling through a shared set of intracellular pathways is a fundamental question in signal transduction. RTK signaling is required for development of the embryonic neural crest, and in numerous cancers arising from this lineage including schwannomas, neurofibromas, and melanomas.
Technology development: Scientific advancement requires the incorporation of novel and robust technical approaches to uncover critical insights. As our interest in tumor heterogeneity necessitated the ability to connect DNA genotype to protein phenotype, we developed a novel pipeline combining targeted single cell DNA sequencing with antibody-sequencing to measure surface protein expression, a technology termed DNA-Antibody sequencing (DAb-seq) that permits joint genotype-phenotype identification in single cells.