Overall Research Objectives:
The primary goal of our research is to understand molecular mechanisms regulating tumor growth, inflammation and metastasis. We are interested in elucidating the signaling cascades that regulate recruitment and activation of immunosuppressive macrophages in the tumor microenvironment during tumor progression. We are using multiple advanced strategies (RNA-seq, ATAC-seq, single cell transcriptomics, immune phenotyping, system biology approaches), human patient samples and genetic mouse models of cancer (pancreatic adenocarcinoma, lung carcinoma, neuroblastoma) to study interactions of myeloid cells with other immune cells and developing tumors. The long-term goal of our research is to translate these findings toward development of novel therapeutics to block immunosuppression in the tumor microenvironment and enhance the efficacy of chemotherapy, radiation therapy and immunotherapy in solid tumors.
Understanding Molecular Mechanisms of Tumor Growth and Metastasis
The primary goal of our research is to understand molecular mechanisms regulating tumor growth, inflammation and metastasis. Our laboratory has longstanding focus on studying signaling cascades that regulate recruitment and activation of immunosuppressive macrophages in the tumor microenvironment during tumor progression. Our lab has defined a novel mechanism by which signals transmitted from the extracellular matrix via the a4b1 integrin and MCSF receptor lead to the activation of Rac2 and Syk which potentially regulate protumerogenic macrophage differentiation and mediates immunosuppression and tumor growth in various solid tumors. An important recent discovery from this study is the identification of Syk kinase and Rac2 as novel targets in macrophages which controls stabilization of hypoxia inducible factor to regulate innate and adaptive antitumor immune responses during tumor growth.
Developing Novel Immune Therapies for Neuroblastoma
Neuroblastoma is an extremely heterogeneous pediatric tumor that arises from neural crest and progression of this tumor is associated with infiltration of immunosuppressive myeloid cells that foster tumor growth and metastasis. How these myeloid cells are recruited and activated in MYCN amplified and non-MYCN amplified pediatric neuroblastoma (NB) tumors is not well understood. Our studies have shown that myeloid cells recruited in neuroblastoma tumors express high levels of BTK and SYK and targeting these kinases can reverse myeloid-mediated immunosuppression and can enhance immunotherapy in mouse model of neuroblastoma. We are currently investigating if these myeloid-targeted therapies can be combined with immunotherapy and or radiotherapy to improve survival of patients with neuroblastoma.
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