# The role of neutrophils in pancreatic cancer pre-metastatic and metastatic niche formation

> **NIH NIH K00** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $97,464

## Abstract

PROJECT SUMMARY:
The interaction between tumor cells and macrophages has been shown to be crucial in promoting tumor
invasion and metastasis. These two cell types are engaged in a paracrine interaction in which tumor-
associated macrophages secrete epidermal growth factor (EGF) to activate tumor cells. In turn, tumor cells
secrete colony-stimulating factor-1 (CSF-1) to which macrophages respond. While soluble factors are well
known to transmit signals between different cells, it is unclear how these soluble mediators can lead to the co-
migration of macrophages and tumor cells away from the high concentration of these factors present in the
primary tumor. Recent studies done in our lab have revealed a novel mechanism of intercellular
communication between macrophages and tumor cells that can transmit signals over long distances through
membranous actin-based tunneling nanotubes (TNTs).These thin actin containing structures form rapidly but
have long lifetimes and can be up to several cell diameters in length. Our preliminary data demonstrates that
the formation of TNTs in macrophages is dependent on actin polymerization, through activation of the
RhoGTPases Cdc42 and Rac1 and their downstream effectors WASP and WAVE. Using FRET-based
biosensors, we have observed differential spatiotemporal activation of Cdc42 and Rac1 indicating that they
play different roles during the formation of TNTs in macrophages. Interestingly, our preliminary data shows that
heterotypic TNTs form between macrophages and tumor cells in co-culture. This novel interaction between
macrophages and tumor cells via TNTs and can induce changes in tumor cell morphology consistent with a
more invasive phenotype. The proposed work to be completed during the F99 phase of this fellowship will be
focused on the regulation of heterotypic TNT formation and dynamics between macrophages and tumor cells,
as well as the role of TNTs in mediating macrophage-dependent tumor cell migration and invasion. We will
determine the structure and mechanism by which TNTs are formed between macrophages and tumor cells.
We will also determine the spatiotemporal activation of RhoGTPases during the formation of heterotypic TNTs
as well as the dependence of TNT formation on the paracrine loop which we know is required for mutual cell
invasion. Importantly, we will analyze the effects of macrophage TNTs on tumor cell function including EGFR
activation, RhoA activation, invadopodia formation, directional migration and invasion. In addition to 2D and 3D
assays, we will employ a newly developed 1D assay that mimics the co-migration of tumor cells and
macrophages along fibers as seen in vivo to determine the role of TNTs in the promotion of long distance
paracrine invasion. Overall, the results of this study will increase our understanding of TNT formation and
regulation in different cell types and determine whether TNTs are required to the persistent long range
migration of macrophages and tumor cells allowing f...

## Key facts

- **NIH application ID:** 10232123
- **Project number:** 5K00CA212451-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Samer Hanna
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $97,464
- **Award type:** 5
- **Project period:** 2018-09-18 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232123

## Citation

> US National Institutes of Health, RePORTER application 10232123, The role of neutrophils in pancreatic cancer pre-metastatic and metastatic niche formation (5K00CA212451-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10232123. Licensed CC0.

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