# Copper-mediated metabolic reprogramming and ECM alterations in TNBC metastasis

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $519,193

## Abstract

Triple negative breast cancer (TNBC) patients present a formidable clinical challenge, as they
exhibit higher rates of metastatic recurrence, and respond poorly to available targeted therapies.
Given the clinical significance, it is imperative to develop effective targeted anti-metastatic
therapies for the treatment of TNBC. Metals serve as co-factors for tumor promoting pathways
and targeting metals to disable these pathways has emerged as a potential anti-cancer therapeutic
strategy. Copper, an essential trace element functions as a catalytic cofactor for a host of
metalloenzymes/proteins that contribute to tumor angiogenesis and metastasis. In addition,
increased copper uptake by malignant cells has led to the development of copper-specific
chelators as therapeutic agents. In a potentially transformative discovery, we have identified
within the primary tumor, a discrete population of highly metastatic OCT4+ SOX2+ cells. We
show that these metastatic cells have significantly elevated levels of intracellular copper and
exhibit increased sensitivity to copper deficiency. We have also shown that copper depletion
alters the architecture of extracellular matrix in the metastatic lungs of both mouse and human.
Our central hypothesis is that copper contributes to two key aspects of metastasis: cancer cell
intrinsic metabolic pathways that directly contribute to metastasis; and the “pre-metastatic niche”
that supports colonization, and outgrowth of disseminated metastatic tumor cells. To test this
hypothesis, we will use pre-clinical models to elucidate cellular and molecular mechanisms of
oral copper chelator tetrathiomolybdate (TM) and leverage banked samples from our completed
phase II TM clinical trial to develop collagen remodeling products as biomarkers of TM response.
The central goal of this proposal is to understand the mechanistic basis of copper depletion as a
viable treatment approach against TNBC metastasis. We expect to make significant advances
through the following aims. Aim 1 will establish the direct link between copper-mediated
metabolic reprograming and metastasis in TNBC and dissect key cellular and molecular
mechanisms, and Aim 2 will investigate how copper deficiency reprograms the extracellular
matrix in the distal metastatic organs to generate an inhospitable microenvironment to impair
metastasis and develop clinically valuable biomarkers of response to TM. Fundamental
discoveries from these integrated pharmacological and genetic investigations has the potential not
only to advance TM into larger randomized trials, but to identify new copper pathways for the
development of novel therapeutic strategies against TNBC.

## Key facts

- **NIH application ID:** 10845266
- **Project number:** 5R01CA257254-04
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Vivek Mittal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $519,193
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845266

## Citation

> US National Institutes of Health, RePORTER application 10845266, Copper-mediated metabolic reprogramming and ECM alterations in TNBC metastasis (5R01CA257254-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10845266. Licensed CC0.

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