# Project 3: The role of microenvironmental metabolites on metastatic progression

> **NIH NIH U54** · ROCKEFELLER UNIVERSITY · 2024 · $183,375

## Abstract

Metabolic programs are particularly relevant during metastasis as it is an inefficient process 
comprising several consecutive steps, with only a small proportion of circulating tumor cells generating a 
metastatic lesion. The inefficiency is largely attributable to the host organ environments, which impose 
metabolic limitations on cancer cells. Indeed, cancer cells are frequently starved for nutrients and oxygen in 
distant organ environments due to poor vasculature. To endure unfavorable nutrient conditions during the 
metastatic cascade, disseminated tumor cells require substantial metabolic rewiring that enables them to 
grow at the primary and metastatic sites. Additionally, cancer cells metabolically interact with each other 
and with normal cell types or upregulate alternative pathways to overcome these metabolic limitations in 
their environment. Integration of nutrient availability from the local environment with metabolic adaptation 
signatures in cancer cells is key to understanding how cancer cells interact with the surrounding cells and 
extracellular nutrients. Furthermore, as re-population of cancer cells at a new organ site creates challenges 
for effective anti-tumor therapeutic strategies, there is an unmet basic and clinical need to better understand 
the molecular interplay between the metastatic site and tumor cells. Therefore, in this proposal, we will test 
the hypothesis that distant organ sites impose metabolic restrictions that cancer cells need to overcome for 
metastatic colonization. To address this, we will employ a comprehensive unbiased approach that combines 
multiple genetic, transcriptomic and metabolomics techniques. These approaches will enable us to dissect 
the metabolic heterogeneity of cancer cells and other cell types in distant organ sites. In the first aim, we will 
systematically map metabolic dependencies of breast cancer cells during colonization of the lung and liver 
using CRISPR-based loss and gain of function approaches. In our preliminary work, we have already 
identified potential candidates that are involved in breast cancer metastasis to lung. In the second aim, we 
will investigate the role of niche cells by combining cell-specific metabolomics and single-cell sequencing 
approaches in multiple metastasis models and in response to therapy. The Birsoy lab has recently pioneered 
the use of metabolism focused CRISPR screens to study multiple aspects of cellular metabolism in cancer 
models. The Cao and Saeed Tavazoie labs have expertise in single cell transcriptomics and computational 
biology. By integrating gene expression profiles and metabolomic information generated by this collaborative 
multidisciplinary effort, our work will provide entry points for identifying pathways that may be activated or 
repressed during the course of metastatic colonization and in response to therapy.

## Key facts

- **NIH application ID:** 11190561
- **Project number:** 3U54CA261701-04S1
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Kivanc Birsoy
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $183,375
- **Award type:** 3
- **Project period:** 2021-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11190561

## Citation

> US National Institutes of Health, RePORTER application 11190561, Project 3: The role of microenvironmental metabolites on metastatic progression (3U54CA261701-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11190561. Licensed CC0.

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