# Prometastatic Effects of Neoadjuvant Chemotherapy in Breast Cancer

> **NIH NIH K99** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $144,439

## Abstract

Project Summary
Metastasis, the dissemination of cancer cells from the primary tumor to secondary sites, is the leading cause of
cancer-related mortality. Although chemotherapy improves overall survival in early breast cancer, it does not
provide definite cure for metastasis. Paradoxically, chemotherapy induces pro-metastatic changes in the tumor
microenvironment if given in the pre-operative (neo-adjuvant) setting. These pro-metastatic changes are
primarily initiated via infiltration of tumors by pro-angiogenic Tie2Hi macrophages, which are essential
components of cancer cell intravasation sites called Tumor MicroEnvironment of Metastasis (TMEM). Only
invasive and migratory cancer cell expressing MenaINV can disseminate via TMEM. In mouse mammary
carcinoma and patient derived xenografts, neo-adjuvant chemotherapy increases (i) TMEM assembly, (ii) the
density of cancer cells expressing MenaINV, (iii) the number of circulating tumor cells, and (iv) lung metastases.
This proposal will elucidate molecular mechanisms by which chemotherapy exerts these pro-metastatic
changes in the breast tumor microenviroment, so that predictive biomarkers and targetable signaling pathways
of “chemotherapy-induced metastasis” can be identified. We hypothesize that macrophages recruited to
tumors upon neo-adjuvant chemotherapy educate tumor cells not only to become dissemination-competent by
inducing MenaINV expression through juxtacrine interactions, but also to obtain tumor-initiating capabilities
responsible for tumor growth initiation at distant sites. In Aim 1, we will investigate whether macrophage-cancer
cell interaction is required for induction of MenaINV and MenaINV-mediated pro-metastatic phenotypes upon
treatment with neo-adjuvant chemotherapy. This will be accomplished using established macrophage depletion
studies in vivo, coupled with advanced microscopy. In Aim 2, we will investigate whether breast tumor cells
expressing MenaINV-Hi also harbor stem cell capabilities. MDA-MB-231 cells expressing a fluorescent stem cell
reporter (SORE6) will be used to generate xenografts for multiphoton intravital imaging microscopy and fixed-
tissue multichannel immune-fluorescent microscopy and study the effects of neo-adjuvant chemotherapy on
tumor cell stemness. Aim 3 is designed to unravel the signaling pathways responsible for the aforementioned
pro-metastatic phenotypes. Transgenic and pharmacological inhibition mouse models targeting the relevant
juxtacrine pathways will be developed to eliminate macrophage-tumor cell interactions and study whether
these pathways are instrumental in chemotherapy-induced metastasis. The research environment at the Albert
Einstein College of Medicine offers outstanding opportunities for collaborations, scientific discussion and
career development. The proposed studies and career development training coupled with an exceptional team
of Dr. Condeelis, expert in advanced microscopy, Dr. Oktay, physician scientist, Dr. Wakefield a pio...

## Key facts

- **NIH application ID:** 10018820
- **Project number:** 5K99CA237851-02
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** George S Karagiannis
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $144,439
- **Award type:** 5
- **Project period:** 2019-09-16 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018820

## Citation

> US National Institutes of Health, RePORTER application 10018820, Prometastatic Effects of Neoadjuvant Chemotherapy in Breast Cancer (5K99CA237851-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018820. Licensed CC0.

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