# Deciphering the Mechanism of Lymphovascular Space Invasion Using a Lymphovascularized Bioengineering Breast Stromal Platform

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $669,122

## Abstract

Highly aggressive cancers are frequently characterized by tumor cell emboli within the lymphatic and blood
vasculature. Termed lymphovascular space invasion (LVSI), this phenomenon has been of high interest to
cancer researchers as it may represent one of the necessary events during progression from a localized to
metastatic cancer. Despite these biological implications, relatively little is known about the mechanisms that
directly enable and promote LVSI formation. Existing in vitro systems lack the multi-tissue and vascular
complexity to model these events. In vivo models, while available, are not amenable to mechanistic studies or
pharmacological screening because of the sheer number of animals required for such experiments. Therefore,
a critical need in the field is to develop models that can faithfully recreate specific phenomena related to
metastatic spread, such as LVSI. Using our novel, multi-cellular, vascularized 3D in vitro platform, we were able
to model intravasation of epithelial emboli and LVSI formation of inflammatory breast cancer (IBC) ex vivo for
the first time. IBC is an aggressive breast cancer variant characterized by extensive LVSI. Gene expression data
from IBC patients identified stromal infiltration and activation as a critical component of LVSI. Using our new in
vitro platform and animal models, we were able to confirm this finding when we discovered that macrophages in
the microenvironment directly promote LVSI formation. Leveraging our new in vitro platform, we propose to
answer three major questions relating to LVSI: What mechanisms promote 1) formation, 2) migration, and 3)
intra-vessel survival of tumor emboli? We hypothesize that LVSI formation is a two-step process where matrix
properties and epithelial marker, E-cadherin which is strongly expressed in IBC, regulate tumor emboli formation
and survival, while the cytokine axis, CCR7/CCL21, homes epithelial emboli to lymphatics. To test this
hypothesis, we propose to use our new in vitro platform in three aims: 1) Determine the role of matrix mechanics
and lymphatic pumping in the temporal kinetics of LVSI, 2) Determine the role of E-cadherin in emboli formation
and survival, and 3) Identify the mechanisms that promote emboli homing to vasculature. Despite the strong
clinical evidence that LVSI is a critical, pre-metastatic phenomenon, our inability to fully recreate LVSI in vitro
has severely limited our mechanistic understanding of responsible pathways. For the first time, our team was
able to recreate LVSI ex vivo using a novel microfluidic platform. Here, we propose to use our in vitro platform
to define the signaling steps that promote LVSI formation and survival in vasculature to better define critical
targets related to cancer progression. To execute the proposal, we have assembled a team composed of experts
in tissue bioengineering, clinical research, and preclinical models of breast cancer. If successful, our work will
offer novel and customizable platfor...

## Key facts

- **NIH application ID:** 10881299
- **Project number:** 1R01CA284102-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Bisrat G Debeb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $669,122
- **Award type:** 1
- **Project period:** 2024-06-04 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881299

## Citation

> US National Institutes of Health, RePORTER application 10881299, Deciphering the Mechanism of Lymphovascular Space Invasion Using a Lymphovascularized Bioengineering Breast Stromal Platform (1R01CA284102-01A1). Retrieved via AI Analytics 2026-08-11 from https://api.ai-analytics.org/grant/nih/10881299. Licensed CC0.

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