# Biology and genetics of metastatic disease

> **NIH NIH R35** · ROCKEFELLER UNIVERSITY · 2022 · $709,351

## Abstract

Biology and Genetics of Metastatic Disease
My laboratory studies the molecular alterations that contribute to metastasis formation, a poorly understood
process and primary cause of solid cancer deaths. It has long been thought that metastasis is caused by
somatic metastasis driver mutations—postulated alterations that have yet to be identified. By showing that
levels of specific microRNAs become altered in metastatic tumors and identifying their target genes, my lab
identified and characterized critical pathways and processes underlying metastasis formation. By studying
germline variants of one such target metastasis gene, we discovered that metastatic potential can also pre-
date tumor formation and be genetically inherited—revealing an unanticipated genetic underpinning for
metastasis and opening up a new direction for the field. Specifically, we determined that two common human
germline variants of the secreted glycoprotein ApoE promote or suppress metastasis in melanoma, with recent
data suggesting this principle may apply to additional cancers. ApoE signaling was found to govern vascular
and immune interactions as well as cellular invasiveness that collectively contribute to metastasis formation.
These insights have significant translational potential and formed the basis of clinical trials that are providing
proof-of-concept for ‘metastasis targeting therapy’, where multiple metastasis regression responses were
observed in advanced stage patients for whom standard of care and immunotherapy treatments had failed.
Going forward, we will use allelic variants of ApoE as powerful genetic entry points to understand the
molecular events underlying metastasis formation, where we will define how ApoE signals are received by
cells and how ApoE mediates intracellular events. We will also extend the concept of hereditary metastasis
genetics to additional cancers and genes, applying our reverse genetic and mouse modeling approaches to
breast and colorectal cancer metastasis. To achieve this understanding, we will employ innovative optical,
physiological, genetic modeling and screening methods to interrogate mouse and human metastatic
transitions. This award will enable our group to establish the first genetically guided framework for
understanding the molecular mechanisms governing metastasis formation—enabling new avenues for its
therapeutic treatment and prevention.

## Key facts

- **NIH application ID:** 10520875
- **Project number:** 1R35CA274446-01
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Sohail F. Tavazoie
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $709,351
- **Award type:** 1
- **Project period:** 2022-09-07 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520875

## Citation

> US National Institutes of Health, RePORTER application 10520875, Biology and genetics of metastatic disease (1R35CA274446-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10520875. Licensed CC0.

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