# The Lung Tumor Microenvironment: Role of Resident Pulmonary Vascular Progenitor Cells in Cancer Progression and Metastasis

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2021 · $218,089

## Abstract

ABSTRACT
Lung cancer remains the leading cause of cancer-related deaths worldwide. While targeted therapies against
oncogenic drivers and immunotherapy approaches have shown promise in reducing the incidence, resistance to
targeted therapies often leads to relapse and progression of disease. In addition, only a relatively small portion
of unselected non-small cell lung cancer (NSCLC) patients respond to mono-immunotherapy. Therefore, novel
therapeutic approaches are urgently needed. Developing new therapeutic strategies requires a better
understanding of the complex interactions between cancer cells and cells within the tumor microenvironment
(TME). The TME is a complex niche of multiple cell types, including immune cells of the innate and adaptive
immune system, cancer-associated fibroblasts, vascular cells, and extracellular matrix (ECM). Defining the
critical cell types and mechanisms whereby cells of the TME regulate cancer progression remains a challenge.
Recently an abundance of studies related to recruited immune cells have emerged. Also, while tumor
angiogenesis is a hallmark of cancer, anti-angiogenic therapy has had limited success for the treatment of lung
cancer, and thus a better understanding of how the vasculature contributes to disease progression is required.
Finally, while the role of cancer stem cells to cancer progression has been well established, the role of stromal
progenitor/stem cells contributing to the TME and cancer progression and metastasis is a completely
understudied area of research. Serendipitous observations made by us through the use of fate-mapping systems
to track vascular smooth muscle cells (SMCs) in the setting of vascular disease demonstrated that mature SMCs
migrate into the outer adventitial layer of the blood vessel and are genetically reprogrammed into a subpopulation
of resident adventitial progenitor cells termed AdvSca1-SM cells. AdvSca1-SM cells are a select subpopulation
of authentic vascular progenitor cells that exhibit multiple fate decisions. AdvSca1-SM cells reside in multiple
vascular beds (e.g. aorta, carotid and femoral arteries, and the pulmonary and coronary arterial vasculature).
Reprogramming is dependent on SMC induction of the transcription factor, Klf4, and AdvSca1-SM cells are the
predominant cell type responding to vessel wall dysfunction, which is dependent on loss of Klf4. Our recent
findings demonstrate that lung AdvSca1-SM cells expand in number, adopt a myofibroblast phenotype, and are
major contributors to lung cancer progression and metastasis. We propose here that cancer cell-mediated
activation of AdvSca1-SM cells results in their differentiation into essential cells of the TME that promote tumor
progression and metastasis. Ablation will blunt, but loss of Klf4 expression will exacerbate tumor growth and
metastasis. Two Aims will test our hypotheses. Aim One will use innovative in vivo fate mapping and in vitro
conditioned media approaches to define the fate of AdvSca1-S...

## Key facts

- **NIH application ID:** 10097362
- **Project number:** 1R21CA255246-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** RAPHAEL A. NEMENOFF
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $218,089
- **Award type:** 1
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10097362

## Citation

> US National Institutes of Health, RePORTER application 10097362, The Lung Tumor Microenvironment: Role of Resident Pulmonary Vascular Progenitor Cells in Cancer Progression and Metastasis (1R21CA255246-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10097362. Licensed CC0.

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