# Kinase signaling during mammary tumor initiation

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2021 · $344,269

## Abstract

PROJECT SUMMARY
Clinical and epidemiological evidence suggests that ~40% of patients with ductal carcinoma in situ (DCIS) left
untreated will progress to invasive breast cancer. However, due to our inability to distinguish lesions that will
progress to invasive cancer from those that will remain non-invasive indefinitely, all DCIS patients are treated
with surgery with or without radiation. This overtreatment dilemma demands the need for individualized patient
care based on biomarkers that predict which patients will progress. Unfortunately, very little is known about
how pre-invasive DCIS cells acquire the ability to invade the adjacent stroma, and how the stroma influences
localized invasion has not been studied. The proposed studies aim to define the molecular interactions
between infiltrating macrophages and pre-invasive epithelial cells, and uncover the mechanisms that promote
tumor development in early stage lesions. Using unique preclinical models of early progression, we show that
macrophages are recruited to pre-invasive lesions that have a high tumor-forming potential, polarized toward a
pro-tumorigenic phenotype, and secrete the cytokine Gas6. We hypothesize that macrophages recruited to
pre-invasive lesions induce cell survival and localized invasion in a Gas6-dependent manner. This hypothesis
will be tested by the following aims: Aim 1: To define the oncogenic potential of Axl during mammary tumor
initiation. Aim 2: To delineate the contribution of paracrine, autocrine and ligand-independent Axl signaling in
early stage lesions. Aim 3: To decipher Axl transcriptional regulatory mechanisms, and identify Gas6-
dependent tumor-promoting pathways. Our studies will utilize several mouse models, a unique xenograft
model of DCIS progression, and a heterotypic 3-D culture system to dissect Gas6-mediated macrophage-
epithelial crosstalk. Significance: The proposed studies will identify a mechanism by which DCIS cells
proliferate and/or invade the basement membrane, and define how the stroma promotes progression to
invasive cancer, addressing major knowledge gaps in the field of premalignancy. Recent studies suggest that
the dissemination of cancer cells occurs as early as the premalignant stage, which begs the need to
understand the mechanisms of cell migration and invasion in early stage lesions. Finally, Gas6 and Axl have
been correlated with poor overall survival and therapy resistance in a number of cancers. Our findings will
significantly advance the fields of DCIS biology and early stage breast cancer progression.

## Key facts

- **NIH application ID:** 10242663
- **Project number:** 5R01CA212518-05
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Heather L Machado
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,269
- **Award type:** 5
- **Project period:** 2017-09-20 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242663

## Citation

> US National Institutes of Health, RePORTER application 10242663, Kinase signaling during mammary tumor initiation (5R01CA212518-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242663. Licensed CC0.

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