# Leader cell development and function in Breast Tumor Collective Migration

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $62,158

## Abstract

Accumulated evidence in human breast cancer and mouse models of breast cancer have shown
that tumor cells invade collectively through the basement membrane (BM) and continue as collective groups
to traverse the collagen-rich ECM to access lymphatic and vascular vessels. Rather than single cells, in the
circulation clusters of heterogeneous circulating tumor cells (CTCs), that also contain tumor-associated
stromal cells such as cancer associated fibroblasts (CAFs), account for >90% of metastases.
 To move collectively requires coordinated cell–cell and cell–matrix interactions. Hallmarks of
collective cell migration include: 1) Cells remain physically and functionally connected such that the integrity
of cell–cell junctions are preserved during movement. 2) A subgroup of cells typically defines the leading
edge, and thus, the direction of collective migration. These are known as “leader “cells and differ in function
from “follower” cells. 3) Collective movement also involves intimate interaction with accessory stromal cells
that release polarity-inducing and pro-migratory factors as well as contribute to path finding by physically
remodeling the surrounding ECM.
 Several hypotheses have been proposed to explain cancer leader cell development during collective
migration. Yet how these leader cells develop, arrive and define the front edge, then lead directed collective
migration, and whether this phenomenon is necessary and sufficient to effect directed collective migration
are largely unknown. We have developed novel microfluidic devices in which to study the collective
migration of primary breast tumor organoids in response to multiple environmental signals
In the present proposal we propose to use primary breast tumor organoids with their inherent cellular
heterogeneity to determine how leader cells develop and function, in response to multiple environmental
signals, so as to direct collective migration. To do so we propose two specific aims. Specific Aim 1. To
determine how K14 leader cells within primary breast tumor organoids polarize to the leading edge and then
function to direct collective migration. Specific Aim 2: To understand chemo-mechanical feedback between
CAF-based ECM remodeling and leader-based invasion.

## Key facts

- **NIH application ID:** 10977366
- **Project number:** 3R01CA254060-03S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Gregory D. Longmore
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $62,158
- **Award type:** 3
- **Project period:** 2022-05-05 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977366

## Citation

> US National Institutes of Health, RePORTER application 10977366, Leader cell development and function in Breast Tumor Collective Migration (3R01CA254060-03S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10977366. Licensed CC0.

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