# Determining the role of SARS-CoV-2 in driving premalignancy of the airway

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $156,000

## Abstract

Project Summary/Abstract
Lung cancer is thought to develop in a stepwise fashion giving us the opportunity to intervene before it becomes
invasive. A novel approach to cure patients of lung cancer is therefore to develop a targeted chemoprevention
strategy to prevent the formation of lung premalignant lesions in the first place. My lab studies airway epithelial
stem cells (AESCs) and the signaling pathways involved in their repair and regeneration after injury. Our studies
led us to the conclusion that premalignancy represents a state of excessive self-renewal of AESCs with a block
in differentiation and we identified several mechanisms involved in stepwise progression to lung cancer. One
such mechanism involves proliferation of AESCs via the Wnt-β-catenin pathway and in particular we found that
only one of the differential phosphorylation sites, the tyrosine Y489 residue of the β-catenin protein, allowed
nuclear localization of β-catenin with concomitant TCF/LEF activation for proliferation. This phosphorylation of
β-catenin at Y489 is not present in normal airway AESCs but persists in premalignant lesions and lung cancer.
 We have developed human and mouse in vitro models of premalignancy in the proximal and distal airway
epithelium by driving Wnt/β-catenin signaling. These models include the air-liquid interface model of proximal
airway stem cell proliferation and differentiation (Aros et al, 2020) and a 3D lung organoid co-culture model with
type I and type II alveolar epithelial cells. We are currently infecting our lung premalignancy models with
SARS-CoV-2, in collaboration with Dr. Arumugaswami at UCLA to assess how viral infection alters this aberrant
response to injury.
 Our hypothesis is that SARS-CoV-2 infection in the setting of premalignancy with excessive proliferation
of AESCs will result in persistent Wnt/β-catenin signaling which will prevent the resolution of premalignant lesions
and allow additional mutations to develop to drive invasive carcinoma. Our goal is to understand the effects of
SARS-CoV-2 on Wnt/β-catenin signaling and especially p-β-cateninY489 in premalignant lesions using the
following approaches:
Specific Aim: To understand the role of SARS-CoV-2 on p-β-cateninY489 in proliferation of AESCs in
premalignant lesions. We hypothesize that p-β-cateninY489 is induced by SARS-CoV-2 for repair after infection
and prevents resolution of existing premalignant lesions.
Specific Aim 1a: We will identify how frequently SARS-CoV-2 infection drives Wnt/β-catenin signaling and leads
to the p-β-cateninY489 in AESCs in proximal and distal airway models.
Specific Aim 1b: We have identified a compound that prevents p-β-cateninY489 in AESCs (Aros et al, 2020) and
will test the effects of this compound on SARS-CoV-2 infected proximal and distal airway premalignancy models.
Specific Aim 1c: We will use transgenic mouse models with loss of β-catenin in the AESCs of the proximal airway
and examine the effects on repair of the airway afte...

## Key facts

- **NIH application ID:** 10148568
- **Project number:** 3R01CA208303-05S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** BRIGITTE N GOMPERTS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 3
- **Project period:** 2016-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148568

## Citation

> US National Institutes of Health, RePORTER application 10148568, Determining the role of SARS-CoV-2 in driving premalignancy of the airway (3R01CA208303-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10148568. Licensed CC0.

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