# Distinct contributions of mesenchymal cell niches in the therapeutic potential of the hedgehog pathway in triple negative breast cancer

> **NIH NIH SC1** · UNIVERSITY OF PUERTO RICO MAYAGUEZ · 2022 · $368,000

## Abstract

Recent studies show that Hedgehog (Hh) signaling correlates with tumor expansion and reduced survival rates
in triple negative breast cancer (TNBC) patients, suggesting a potential therapeutic value for Hh inhibitors.
Several studies have highlighted mesenchymal cells as potential targets in the tumorigenicity of Hh signaling,
yet their diagnostic value and influence in the therapeutic response of Hh inhibitors have not been established.
A main limitation is the lack of models that capture distinct contributions of mesenchymal cell sub-types in the
growth response to Hh inhibitors. Inhibition of Hh signaling can lead to tumor expansion or suppression; a bi-
modal growth mechanism that can negatively impact the therapeutic outcome in tumors treated with Hh
inhibitors. Our studies and preliminary data support the influence of mesenchymal cell sub-types in the
tumorigenic potential of Hh signaling. Our evaluation of individual contributions of fibroblasts and mesenchymal
stem cells suggest that changes in the composition of the mesenchymal niche influence tumorigenic signals of
the Hh pathway and response to Hh inhibitors. Our long-term goal is to provide biomimetic and multi-cell type in
vitro models that enable the identification of new targets in clinically challenged endocrine tumors. Our overall
goal is to validate an in vitro model for prediction of therapeutic efficacy and identify oncogenic cues associated
to the composition of the stroma that can be used as oncogenic markers and targets to improve therapeutic
response to Hh inhibitors. Our central hypothesis is that the oncogenicity of Hh signaling is regulated by the
composition of the adjacent stroma. Our hypothesis has been formulated based on previous studies and our
preliminary data supporting distinct contributions of mesenchymal cell sub-types in the response of tumor cells
to Hh signaling. Our rationale is that the evaluation of the interplay between the mesenchymal and immune cell
niches in the sensitivity of tumors to Hh inhibitors will be valuable towards understanding tumor transitions to
therapeutic resistance driven by the stroma. The following aims are proposed: Aim 1- Model paracrine Hh
signaling contribution to stemness and resistance to therapy, Aim 2- In vivo validation of a Hh paracrine model
through evaluation of response to Hh inhibition, and Aim 3- Impact of immune cells in the oncogenicity of Hh
paracrine signaling. These aims will support recapitulation of in vivo observations in our in vitro models and
confirm the influence of the mesenchymal cell niche in the tumorigenicity of Hh signaling. This contribution is
significant as it will provide new biological insights into the modulation of tumor cell behavior in response to
shifts in the stromal niche and establish the therapeutic value of stromal cell components in Hh
signaling. The technology is innovative because it provides with a simple and customizable culture model in
which to evaluate tumor transitions towar...

## Key facts

- **NIH application ID:** 10459462
- **Project number:** 5SC1GM131967-03
- **Recipient organization:** UNIVERSITY OF PUERTO RICO MAYAGUEZ
- **Principal Investigator:** Maribella Domenech
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,000
- **Award type:** 5
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459462

## Citation

> US National Institutes of Health, RePORTER application 10459462, Distinct contributions of mesenchymal cell niches in the therapeutic potential of the hedgehog pathway in triple negative breast cancer (5SC1GM131967-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10459462. Licensed CC0.

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