The rockefeller university

Metastasis is a fascinating biological process that causes most 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 uncovered surprising fundamental insights into mechanisms of gene regulation.

Metastatic disease causes most cancer deaths but remains poorly understood at the molecular level. The Tavazoie lab studies the molecular and cellular mechanisms underlying this process.

How do rare cancer cells initiate metastases in end-organs? How do metastatic cells reprogram surrounding host cells’ gene expression and metabolic states? How do cells evade the immune system? How are extreme metastatic gene expression states that enable all of this established? The lab tackles these questions by first employing genome-wide technologies to identify recurrent molecular alterations associated with metastasis. Molecular and genetic studies in mice identify critical genes that regulate this process, with clinical association studies confirming human relevance and biochemical studies implicating molecular pathways involved. This has led to the discovery that modulation of tissue-specific sets of non-coding RNAs drive metastasis formation in distinct cancer types by altering expression levels of critical downstream genes that alter the cellular, metabolic, or matrix composition of the metastatic microenvironment. Such changes to the microenvironment enhance the survival, immune-evasive, and invasive capacity of cancer cells. These studies have uncovered the first evidence for an inherited genetic basis for human metastasis formation—providing a powerful genetic foundation for uncovering the genetic basis of metastasis by various cancer types and providing a genetic link between metastasis and Alzheimer’s disease, which the lab is studying. Scientists in the lab have applied these insights toward the development of two first-in-class metastasis-targeting therapeutics, which have been advanced into national clinical trials. Their long-term goal is to develop broadly curative metastasis-preventive regimens for common cancers.

By studying how rare cancer cells achieve extreme gene expression programs during metastasis formation, Tavazoie and his colleagues have revealed that modulation of specific tRNAs is a gene regulatory process that alters the expression of specific downstream proteins in a codon-dependent manner to causally drive cancer progression. This has led to the delineation of specific tRNA-driven pathways as well as demonstration that restriction of specific amino acids can govern codon-dependent translation of specific genes. Such tRNA modulation responses have been observed in a variety of cells and systems and are increasingly recognized as a key mode of gene regulation.

Tavazoie is a faculty member in the David Rockefeller Graduate Program, the Tri-Institutional M.D.-Ph.D. Program, and the Tri-Institutional Ph.D. Program in Computational Biology & Medicine.