# Three-dimensional organoid models to study breast cancer progression

> **NIH NIH R37** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $403,713

## Abstract

Abstract
Approximately 20% of breast cancers detected through mammography are pre-invasive Ductal Carcinoma in
situ (DCIS). If left untreated, approximately 20-50% of DCIS will progress to more deadly Invasive Ductal
Carcinoma (IDC). No prognostic biomarkers can reliably predict the risk of progression from DCIS to IDC. Similar
genomic profiles of matched pre-invasive DCIS and IDC suggests that the progression is not driven by genetic
aberrations in DCIS cells, but microenvironmental factors, such as hypoxia and metabolic stress prevalent in
DCIS, may drive the transition. We need innovative models to investigate how to halt steps of DCIS progression
to invasive phenotypes and subsequent metastasis from the primary site. This proposal directly addresses
this unmet need by developing a novel three-dimensional in vitro organoid model that recapitulates key
hallmarks of DCIS to IDC progression: tumor-size induced hypoxia and metabolic stress, tumor heterogeneity
and spontaneous emergence of migratory phenotype in the same parent cells without any additional stimulus. A
tangible advantage of the proposed organoid models is the ability to precisely and reproducibly study how the
hypoxic microenvironment induces tumor migration in real time and in isolation from non-tumor cells present in
vivo, providing unique opportunity to define tumor-intrinsic mechanisms of DCIS to IDC progression.
During July 2018-Feb 2022 ESI MERIT Award period, we have shown that inhibition of tumor-secreted factors
effectively halts organoid migration, while inhibition of hypoxia is effective only within a time window and is
compromised by tumor-to-tumor variation, supporting our notion that hypoxia initiates migratory phenotypes but
does not sustain it. We have also analyzed secretome from metastatic breast cancer pleural effusion showing
significantly higher levels of CCL2/MCP1, CXCL10/IP10, IL-6, IL-8, regulatory IL-10, and IL-7 and IL-15.
Strategies to neutralize these key cytokines may generate anti-tumor responses in the pleural environment.
Microarray analysis of hypoxia-induced migration and secretome-induced migration suggested role of Rho
GTPase and PI3K/AKT signaling pathways in maintaining migration. Our results show that hypoxic organoid
models exhibit partial EMT signatures as early as day 1, which is maintained as these non-migratory organoids
transition to migratory phenotypes.
During the two-year extension period, we will continue 1) to optimize our DCIS models incorporating ductal
structure and other components from DCIS microenvironments; 2) to test new mechanisms linking tumor-intrinsic
hypoxia, partial/hybrid EMT and collective migration; 3) to inhibit signaling mechanisms to halt emergence of
migratory phenotypes.
The successful completion of the proposed work will provide answers to two fundamental questions in the
progression of invasive breast cancer: 1) What causes some DCIS cells to become migratory and develop into
invasive tumors? 2) How and where ...

## Key facts

- **NIH application ID:** 10928084
- **Project number:** 5R37CA232209-07
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Shilpa Sant
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $403,713
- **Award type:** 5
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928084

## Citation

> US National Institutes of Health, RePORTER application 10928084, Three-dimensional organoid models to study breast cancer progression (5R37CA232209-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10928084. Licensed CC0.

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