# Tumor cell -TAM Paracrine Signaling in Breast Cancer

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $430,489

## Abstract

ABSTRACT
Immune checkpoint inhibitors are FDA approved for metastatic triple negative breast cancer (TNBC) and work
well for patients with high levels of tumor infiltrating lymphocytes (TIL), but for the majority of BC patients, these
agents are ineffective. Continued research is needed to elucidate the interplay between tumor cells and the
diverse immune cell populations within the primary TME, and how this interaction shapes tumor biology. Tumor-
associated macrophages (TAM) represent one of the most abundant immune components in BC TME and exhibit
a robust and unique influence on the disease. High levels of TAM infiltration are associated with poor prognosis
in BC. TAMs play a critical role in a wide range of pro-tumorigenic, pro-metastatic activities including tumor
angiogenesis, extracellular matrix (ECM) remodeling, immunosuppression, and chemoresistance. How to
surmount TAM infiltration and function in order to activate a potent anti-tumorigenic and anti-metastatic response
represents a gap in knowledge for the BC field. TAMs most closely resemble M2-polarized type macrophages
and exhibit some overlapping functions between the categories. TAMs are a highly heterogeneic, plastic cell
population endowed with tumor-promoting functionality measured by the overall abundance of M2 vs M1
markers. TAM polarization and immunosuppressive capacities are dependent upon where these cells are located
and what signals are received within the TME. Whereas M2-like polarization is considered pro-tumorigenic, M1-
like polarization is associated with inflammatory, anti-tumor effects and improved prognosis. Tumor cells
generate paracrine signals that recruit and regulate TAM function. In turn, TAMs produce signals that affect the
metastatic potential of tumor cells. Given the clear pro-tumor and metastatic roles of TAMs, it seems evident that
identifying ways to abrogate pro-tumorigenic M2-like responses and promote anti-tumorigenic M1-like responses
in BC will be clinically advantageous. However, effective strategies remain elusive. Our proposal introduces a
new strategy to target a kinase called HUNK that has the potential to be more advantageous than strategies that
directly target TAMs. Targeting HUNK will have a multifaceted effect by not only halting pro-tumor/metastatic
tumor intrinsic signaling but also fundamentally changing the “feed forward” paracrine loop between tumor cells
and TAMs.

## Key facts

- **NIH application ID:** 10808082
- **Project number:** 5R01CA269508-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Elizabeth Yeh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $430,489
- **Award type:** 5
- **Project period:** 2023-03-13 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808082

## Citation

> US National Institutes of Health, RePORTER application 10808082, Tumor cell -TAM Paracrine Signaling in Breast Cancer (5R01CA269508-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10808082. Licensed CC0.

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