Metastasis, the spread of cancer cells from a primary tumor to distal organs, accounts for the overwhelming majority of human deaths from solid cancers. Dr. Tavazoie’s laboratory employs a systems biological approach that integrates molecular, cellular, animal, and clinical observations to identify and characterize key molecular regulators of this complex process, with the goal of developing novel therapies aimed at its prevention and treatment.

This year, over eight million people will die from cancer globally. For many, the cause of death will be metastatic colonization of distant organs by cancer cells. As is the case with developmental programs, metastatic progression requires the proper expression of effector genes that drive specific cellular and cell-biological phenotypes. Dr. Tavazoie is a cancer biologist and medical oncologist interested in how such prometastatic gene expression programs are established in cancer cells, how they enable cancer cells to metastasize, and how such programs emerge during cancer progression. These studies have not only revealed molecular pathways that govern metastatic progression, they have also provided basic insights into previously undescribed mechanisms of gene expression regulation by non-coding RNAs.

Dr. Tavazoie’s laboratory employs molecular, genomic, biochemical, genetic, imaging, and computational approaches to study this process. These insights, combined with in vitro, in vivo, genetic, and clinical association observations, generate an integrated molecular and biological model of metastatic progression. This systematic approach has revealed that the acquisition of the metastatic phenotype by breast cancer cells requires the silencing of specific small noncoding RNAs (microRNAs), leading to the enhanced expression of metastatic promoters. Dr. Tavazoie’s lab has shown this to be the case in other prevalent cancers, such as melanoma and colorectal cancer. By experimentally modulating these metastasis regulatory microRNAs, the metastatic activity of cancer cells can be strongly impacted. Importantly, the expression levels of these specific microRNAs and their target genes in human cancer specimens support their functionally implicated roles in cancer.

With these microRNAs, Dr. Tavazoie’s lab can efficiently uncover their cellular phenotypes and implicate their downstream target genes and pathways as novel effectors of metastatic progression. His lab has established mouse metastasis systems that model the progression of prevalent human cancers, such as triple negative breast cancer, melanoma, and colorectal cancer. These cancers were chosen because of their large impact globally; the lack of targeted therapies to prevent their progression; and their distinct developmental lineages leading to common outcomes. To ensure the generality of their conclusions, Dr. Tavazoie’s lab uses xenograft, patient-derived xenograft, immunocompetent, and genetically initiated models.

Dr. Tavazoie’s overarching goals are to systematically identify the gene networks downstream of these and other small RNA regulators; to determine how these small RNAs are modulated during the acquisition of metastatic capacity; to uncover the roles of these regulators and their target genes in cancer, and in normal physiology or development; and to identify and therapeutically target key vulnerabilities within these networks in cancer. His lab’s discovery of novel small RNAs, including a new class of RNA fragments arising from transfer-RNAs, expands the reach of this work to diverse classes of non-coding RNAs. These studies are revealing previously uncharacterized mechanisms of gene expression regulation in normal cells and could open new avenues for therapeutic intervention in patients at risk for metastatic relapse.