Sohail Tavazoie, M.D., Ph.D.
Leon Hess Professor
Senior Attending Physician
Metastasis is responsible for the majority of cancer deaths. The Tavazoie laboratory employs a systems biology approach that integrates molecular, genetic, cellular, organismal, and clinical observations to discover and characterize key molecular regulators of metastasis, with the goal of developing new therapeutics for its prevention and treatment. This work has also unexpectedly uncovered fundamental insights into mechanisms of gene regulation.
Metastatic disease is the primary cause of cancer mortality but remains poorly understood at the molecular level. The Tavazoie lab studies the molecular and cellular mechanisms underlying this process. Their work on metastasis has also uncovered previously unknown and fundamental mechanisms of gene regulation.
The lab employs unbiased genome-wide technologies to identify recurrent molecular alterations associated with enhanced metastatic capacity. Molecular and genetic studies in mice are used to implicate causal and critical genes that regulate this process, with clinical association studies confirming human relevance and biochemical studies implicating signaling pathways involved. This has led to the discovery that modulation of tissue-specific sets of small non-coding RNAs (microRNAs) drives metastasis formation in distinct cancer types by altering expression levels of critical downstream genes. These genes activate pathways that alter the cellular, metabolic, or matrix composition of the metastatic microenvironment; changes to the microenvironment enhance the survival, immune-evasive, and invasive capacity of cancer cells. Major efforts in the lab aim to understand how metastases initiate and how extreme metastatic gene expression states are established, and explore the role of hereditary genetics in governing metastatic potential. The lab’s findings have been applied toward the development of first-in-class metastasis-targeting therapeutics, which are currently in national clinical trials. Their long-term goal is to develop broadly curative metastasis-preventive regimens for common cancers.
Furthermore, by studying how rare cancer cells are able to achieve extreme gene expression programs that enable metastasis formation, Tavazoie and his colleagues have gained basic insights into gene regulatory mechanisms. For example, dynamic modulation of specific transfer RNAs (tRNAs) has been shown to alter the expression of specific downstream proteins and to drive cancer progression. This has led to the discovery of specific tRNA-driven pathways. Moreover, mechanistic insights into gene regulation by an unusual class of small-RNAs, called tRNA-fragments, have also been uncovered. In addition to their relevance for metastatic disease, these basic studies are providing fundamental new insights into gene regulation mechanisms.