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The focus of our research program has been the biology of cancer metastasis. In this context, our work has centered on the role of the microenvironment (ME) in liver metastasis (LM) of GI cancers. Our overarching goal has been translational and our aim has been to identify targets and develop therapeutic interventions to block the spread of malignant disease to, and within the liver. In the course of these studies, our research team was among the first to show that cancer cells entering the liver induce a rapid inflammatory response resulting in a cytokine cascade that enables trans-endothelial migration and liver colonization. We also showed that in this TNF-飦� rich ME, the metastatic cells can escape death through autocrine IL-6/STAT3 signaling. We identified The TNF receptor 2 (TNFR2) as a survival factor for regulatory T cells and myeloid-derived suppressor cells in the immune-tolerant ME (IME) of colon cancer LM. This work led to the identification of a sexual dimorphism in the control of the liver IME and the discovery of the important role that estrogen plays in this regulation. Our lab was also among the first to document the importance of the IGF-axis to cancer cell invasion and metastasis in general, and LM, in particular. Several strategies for targeting the IGF-axis were developed, leading to the bioengineering of the IGF-Trap - a potent inhibitor of growth and metastasis of several aggressive cancers including pancreatic ductal adenocarcinoma (PDAC). We subsequently found that the IGF-Trap affects the innate immune response to metastatic cells in the liver, blocking the polarization of infiltrating neutrophils to an immunosuppressive N2 phenotype and profoundly changing the immune landscape associate with LM. We subsequently optimized a combinatorial immunotherapy for the prevention and treatment of PDAC LM consisting of the IGF-Trap and anti PD-1 antibodies. More recently we reported that the IGF-Trap when encapsulated in nanoparticles and administered systemically in mice bearing intracranial glioma tumors, could inhibit the growth of these tumors and extend survival. The IGF-technology has been patented and we are making progress towards eventual translation to the clinic for the treatment of specific malignant indications. In addition, our work on the biology of PDAC was recently extended to identifying and targeting a promoter of PDAC initiation and progression (IMP-1) and its regulated transcripts.