# Targeting Musashi-2 (MSI2) regulation of VEGFR2/VEGF-A in lung cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $376,547

## Abstract

The goal of this proposal is to understand how changes occurring during metastasis of non-small cell lung
cancers (NSCLC) promote aggressive phenotypes and drug resistance. Comparison of cell line panels derived
from non-metastatic versus highly metastatic tumors of the KrasLA1/+; P53R172HΔG/+ (KP) mouse model, which
simulates human NSCLC, identified upregulation of Musashi-2 (MSI2) as one of the most consistent features of
metastatic cells. From analysis of two independent sets of primary human tissue specimens, we determined
that MSI2 expression is significantly elevated during tumor progression. Using six independent metastatic
murine and human NSCLC cell line models, we demonstrated that MSI2 is essential for NSCLC invasion and
metastasis in vitro and in vivo. Candidate pathway analysis and reverse-phase protein array (RPPA) screening
identified EMT-associated proteins including the TGF-β type I receptor (TGFBRI), SMAD3, claudins, and the
vascular endothelial growth factor receptor (VEGFR2) as strongly regulated by MSI2 in NSCLC. We directly
demonstrated a functional role for several of these proteins in MSI2-induction of invasion. This proposal
focuses on MSI2 regulation of VEGFR2 and its ligand, VEGF-A, given the established importance of VEGFR
signaling in NSCLC, and the clinical interest of drugs targeting this pathway.
We hypothesize that autocrine MSI2 regulation of VEGFR2 and VEGF-A is important for NSCLC invasion,
signaling and angiogenesis, and paracrine MSI2 regulation of these proteins supports tumor angiogenesis. In
this proposal, we will complement investigations of MSI2 regulation of VEGF signaling with preclinical studies
addressing the importance of targeting MSI2 and VEGF signaling pathways to yield improved treatment
strategies for NSCLC. In Aim 1, we will use in vitro experiments to define the autocrine and paracrine
consequences of MSI2 regulation of VEGF downstream signaling. We will test if MSI2 regulates VEGFR2-
dependent signaling and growth of NSCLC cells in hypoxia and whether MSI2 tumor expression affects
endothelial cells growth in co-culture experiments, mechanism of MSI2 regulation of target mRNAs and
evaluate relevant candidate signaling intermediates. In Aim 2, we will establish the role of MSI2-VEGF
signaling in tumor growth, vascularization and invasion using both orthotopic xenograft models and in MSI2-KP
transgenic mice and in human tissue microarrays. In Aim 3, we will evaluate MSI2 as a regulator of response to
VEGFR2/VEGF-A inhibitors (specifically cabozantinib, and bevacizumab in combination with carboplatin) and
as a drug target. In order to determine whether MSI2 is a useful drug target, we will test novel specific
compounds targeting MSI2 for control of NSCLC.

## Key facts

- **NIH application ID:** 10133313
- **Project number:** 7R01CA218802-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Yanis Boumber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,547
- **Award type:** 7
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133313

## Citation

> US National Institutes of Health, RePORTER application 10133313, Targeting Musashi-2 (MSI2) regulation of VEGFR2/VEGF-A in lung cancer (7R01CA218802-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133313. Licensed CC0.

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