# (PQ1) Progenitor cell malfunction, mutations and changes in microenvironment: A dynamic risk spectrum for cancer evolution

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $502,882

## Abstract

Project Summary/Abstract
 In this proposal we will address the provocative question (PQ1): “For tumors that arise from a
premalignant field, what properties of cells in this field can be used to design strategies to inhibit the
development of future tumors?
 We will focus on squamous cell lung cancer (SCC), a common cause of cancer mortality and a
neoplasm for which there is considerable evidence supporting an origin from a premalignant field. We propose
to answer this question through a comprehensive strategy that focuses on three critical elements of the
premalignant field for SCC of the lung: epithelial progenitor cell function, which is required for repair and
maintenance of a healthy epithelium; genomic alterations in premalignant dysplasias; and the composition
and function of the microenvironment. We hypothesize that “Evolution of lung cancer from a field of
premalignant dysplasia is driven both by intrinsic changes in epithelial progenitor cells as well as
changes that occur in the field microenvironment. Thus, therapy could be targeted to rescue functions
of epithelial progenitor cells and/or to restore the microenvironment.” We propose three aims to address
this hypothesis. Aim 1. Mechanisms of progenitor malfunction to identify new targets for
chemoprevention: We will determine whether epithelial progenitor malfunction in terms of self-renewal and
multipotentiality varies across a dysplasia spectrum. We will also assess whether progenitor response to the
chemopreventive agent iloprost differs across this dysplasia spectrum. RNA sequencing will explore
determinants of progenitor dysfunction and response to iloprost, potentially identifying novel interventions and
predictive biomarkers. Aim 2. Detecting novel genomic changes to identify new targets for
chemoprevention: We will assess whether the genetic and epigenetic profile of dysplasia varies across the
above dysplasia spectrum. Brushings collected from the same dysplasia spectrum will be used to identify
mutations, epigenetic alterations and transcriptomal changes; all compared to the tumor in those subjects with
SCC. Targetable mutations and pathways will be identified. Aim 3. Changes in composition and function of
microenvironment to identify new targets for chemoprevention: We will assess whether the
microenvironment varies across the above dysplasia spectrum. Mass cytometry will be used to characterize
cells that constitute the field microenvironment. We will also explore cellular heterogeneity in the field in a
subset of dysplasias with known history of persistence/progression or regression using single cell
transcriptomic profiling of flow-sorted epithelial and non-epithelial cells. Identification of intervention targets,
such as immune checkpoints, inflammation and angiogenesis will be our goal. We anticipate that our
integrative approach will lead to new strategies to prevent the evolution of premalignancy to invasive SCC.

## Key facts

- **NIH application ID:** 10251890
- **Project number:** 5R01CA219893-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Moumita Ghosh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,882
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251890

## Citation

> US National Institutes of Health, RePORTER application 10251890, (PQ1) Progenitor cell malfunction, mutations and changes in microenvironment: A dynamic risk spectrum for cancer evolution (5R01CA219893-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10251890. Licensed CC0.

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