# A Bioengineered Model of Tumor Vessel Interactions in Pancreatic Cancer

> **NIH NIH R21** · CORNELL UNIVERSITY · 2022 · $183,164

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths among malignancies. PDAC is
highly invasive and forms metastases in distant organs at the very early stage of tumor progression. To better
understand PDAC metastasis, tumor-blood vessel interactions need to be evaluated further, as tumor cells
spread primarily through the blood circulation. However, how PDAC interacts with blood vessels and establishes
distant metastases are poorly understood. Recently, our study using both three-dimensional (3D) biomimetic
PDAC-on-chip and multiple in vivo mouse models showed that PDAC cells invaded blood vasculatures and
actively replaced endothelial cells via ALK7 signaling, leading to a formation of tumor-vessel hybrid structure in
PDAC tumors. We refer to this phenomenon as tumor vessel replacement. Despite the novelty of the finding, it
is unknown what the biological consequences of the tumor vessel replacement in PDAC are. Understanding the
phenotypic consequences of the tumor vessel replacement is critical to determine the clinical relevance and
significance of blocking ALK7 in PDAC. We hypothesize that PDAC tumor vessel replacement increases tumor
vessel permeability; then promotes tumor intravasation and metastasis by facilitating tumor cells’ entering the
blood circulation through the leakier vessels. In order to test these hypotheses, we aim to determine—in both in
vitro and in vivo—(i) if tumor vessel replacement induces tumor vessel leakiness and promotes metastatic
dissemination and (ii) if ALK7 inhibition or ALK7 knock out (KO) ameliorates or reverses tumor vessel leakiness
and metastasis. In Aim 1, we will assess the role of ALK7 in PDAC vessel permeability in pericyte-covered blood
vessel on-chip by co-culturing microvascular endothelial cells and pericytes to mimic physiological blood vessels
surrounded by pericytes (Aim 1.1). Next, we will evaluate the role of ALK7 in PDAC vessel dysfunction in vivo.
We will generate an orthotopic PDAC model using wild-type or ALK7-KO PDAC cells, and examine PDAC tumor
vessel permeability by intravenously injecting dextran molecules (Aim 1.2). In Aim 2, we will examine ALK7 in
PDAC metastasis in vitro by establishing pre-metastatic liver microenvironment in the reservoirs that are
connected to the engineered blood vessel. Multiple PDAC lines will be assessed to test whether ALK7-mediated
tumor vessel replacement affects metastatic spreading (Aim 2.1). We will then evaluate the role of ALK7 in PDAC
metastasis in vivo using human patient-derived xenograft (PDX) models in collaboration with Dr. Manuel Hidalgo.
Metastatic tumor burdens in control vs. ALK7 KO groups will be assessed, and the number of circulating tumor
cells and overall survival rate will be determined (Aim 2.2). In summary, our 3D PDAC-on-chip system will provide
a unique platform to better investigate PDAC interactions with blood vessels and metastatic progression. We will
decipher the roles of ALK7 signaling in mediating...

## Key facts

- **NIH application ID:** 10373531
- **Project number:** 1R21CA252162-01A1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Esak Lee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $183,164
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10373531

## Citation

> US National Institutes of Health, RePORTER application 10373531, A Bioengineered Model of Tumor Vessel Interactions in Pancreatic Cancer (1R21CA252162-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10373531. Licensed CC0.

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