# Environmental Regulation of Cancer Stem Cell Plasticity in Metastasis

> **NIH NIH U01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $625,201

## Abstract

Cancer stem cells, the key population driving growth and metastasis of triple-negative breast cancer and other
breast carcinomas, exist in states with epithelial and mesenchymal phenotypes. Mesenchymal breast cancer
stem cells drive local invasion and metastatic spread, while cancer stem cells transition to an epithelial state to
proliferate in primary and metastatic sites. Reversible transitions from epithelial to mesenchymal (EMT) and
mesenchymal to epithelial (MET) states of cancer stem cells drive tumor progression, underscoring the critical
need to understand mechanisms driving these transitions in tumor environments. We hypothesize that
extracellular matrix proteins and mechanical stress regulate epithelial and mesenchymal transitions of triple
negative breast cancer stem cells in distinct compartments in the metastatic cascade: primary tumor,
intravascular, and bone/bone marrow metastases. To systematically interrogate this hypothesis, we will employ
a physical sciences approach based on precisely tunable tissue-engineered tumor environments pioneered by
our group. We have developed a novel polymeric scaffold architecture that maintains functional conformations
of key extracellular matrix proteins present in primary breast tumors while independently controlling elastic
modulus of the engineered primary tumor environment. Preliminary studies show these scaffolds control EMT
and MET phenotypes of human breast cancer cell lines and cancer cells obtained directly from patients. To
analyze EMT and MET states of cancer cells in the vasculature, we will use an innovative, label-free
microfluidic device to capture circulating tumor cells. We also will subject circulating tumor cells to a recently
identified intravascular mechanical and chemical stress, neutrophil extracellular traps (NETs), using a new
technology we developed to artificially reproduce NETs in vascular mimetic microchannels. Finally, we will
simulate components of the bone/bone marrow metastatic environment in vivo using implanted scaffolds with
osteogenic cells and mesenchymal stromal cells. For all aspects of this research, we will image dynamics of
EMT and MET plasticity with a newly designed fluorescent reporter system. We will quantify effects of
engineered tumor environments on EMT and MET states of breast cancer stem cells through these specific
aims: 1) investigate effects of extracellular matrix proteins and mechanical stress on stem cell plasticity in a
primary tumor; 2) establish dynamics of EMT and MET in circulating tumor cells interacting with NETs; and 3)
determine cell-environmental interactions driving transitions of cancer stem cells metastatic to bone. Through
an integrated, multi-disciplinary approach, we will establish functions of physical components of tumor
environments on plasticity of triple-negative breast cancer stem cells, which we expect will lead to new
treatment options to target this aggressive disease.

## Key facts

- **NIH application ID:** 10149963
- **Project number:** 5U01CA210152-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** JOERG LAHANN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $625,201
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149963

## Citation

> US National Institutes of Health, RePORTER application 10149963, Environmental Regulation of Cancer Stem Cell Plasticity in Metastasis (5U01CA210152-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10149963. Licensed CC0.

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