Instructor, Department of Developmental & Molecular Biology
We are interested to delineate the role of receptor tyrosine-kinase-regulated miRNAs in macrophage-mediated enhancement of mammary tumor progression and metastasis in vivo.
Tumor-associated macrophages (TAMs) promote mammary tumor progression and metastasis and the CSF-1/CSF-1R blockade inhibits the appearance of TAMs. CSF-1R inhibitors, useful for the treatment of breast cancer, have advanced to Phase I/II clinical trials. However, because of their possible side effects on other CSF-1-regulated processes, it is desirable to identify new molecular targets acting downstream of the CSF-1R. Using genome-wide transcriptome profiling combined with bioinformatics, immunological and biochemical studies, we have demonstrated that CSF-1R pTyr-721 signaling causes up-regulation of a validated oncomir overexpressed in breast cancer. Direct inhibition of this microRNA may not be appropriate in humans due to the high number (i.e >200) of transcripts targeted by this microRNA, some necessary for normal cellular functions. Thus, we are investigating whether inhibition of this CSF-1-regulated miRNA expression alone, or blockade of particular miRNA targets abolish or significantly reduce the macrophage enhancement of tumor progression and metastasis in vivo.
We are currently focusing on 1) determining the CSF-1R pTyr-721 signaling pathways regulating the expression of this microRNA in macrophages, 2) the identification and validation of the microRNA gene targets regulated downstream of CSF-1R pTyr-721 signaling and their function in macrophages and 3) investigating the function of this CSF-1R pTyr-721-dependent microRNA in tumor progression and metastasis in vivo. Evaluating the contribution of a new candidate molecule and of its downstream targets provides new avenues for treatment of cancer progression to metastasis and has informative value for addressing the necessity of combined or alternating therapeutics at different metastatic stages.
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
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