# Elucidating the evolution of Krt8+ alveolar cells to Kras-mutant lung preneoplasia and cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $596,247

## Abstract

PROJECT SUMMARY
A significant fraction of lung adenocarcinomas (LUADs) in lifetime smokers harbor somatic mutations in the
KRAS oncogene (KM-LUADs). Due to enhanced screening, KM-LUAD is increasingly being detected at earlier
pathological stages, thus posing a growing public health burden that warrants improved early treatment.
Despite this urgency, early changes that conceive KM-LUAD and that would thus likely comprise ideal targets
for interception remain poorly characterized. Previously, our group and others have shown that tobacco
exposure leads to a pervasive field of injury that is composed of molecular (e.g., KRAS mutations) and
inflammatory changes in normal-appearing epithelium and in the lung, and that are prevalent in the LUADs
themselves. We and others have also previously described molecular and immune changes, including a
decrement in host immunity, that are associated with development of lung premalignant lesions (PMLs) and
KM-LUAD. These earlier studies have shed light on events that are likely implicated in early lung tumor
development. Yet, especially for a cancer like KM-LUAD that is causally related to smoking, the identity and
properties of specific cell populations that trigger a field of injury as well as its progression to PML and KM-
LUAD are not known. In our preliminary efforts, we performed single-cell RNA-sequencing of lung tissues from
a human-relevant mouse model of tobacco-associated KM-LUAD. We found a population of Krt8+ alveolar
cells (KACs) that was greatly increased early on in lungs exposed to tobacco carcinogen but not control saline
and that were also associated with tumor cell onset. KACs displayed intriguing properties that allow us to
surmise that they perhaps represent KM-LUAD progenitors: they amassed the same driver Kras mutations
found in the resultant LUADs; they expressed transcriptomic programs and cell-cell interactions that are highly
pertinent to KM-LUAD including augmented p53 as well as pro-inflammatory IL-1β and NF-κB signaling; and
their expression profiles were highly enriched in human PMLs and LUADs. We also found that KACs were
markedly increased in the human LUAD ecosystem relative to matched normal lung. Our preliminary findings
motivate the hypothesis that oncogenesis of KACs in concert with pro-inflammatory signaling mediated
by IL-1β/NF-κB underlie initiation and development of PML and KM-LUAD. To address our hypothesis we
will 1) characterize at single-cell resolution evolution of KACs to PML and KM-LUAD, as well as determine the
role of p53 signaling in this process; 2) discern the role of pro-inflammatory signaling in promoting evolution of
KACs to PML and KM-LUAD; and 3) use multiple approaches including drug screening to determine whether
targeting KACs will intercept PML and KM-LUAD development. At the conclusion of our studies, we will have
unraveled novel paths in the phenotypic evolution of KM-LUAD as well as laid the foundation for development
of new strategies that inhibi...

## Key facts

- **NIH application ID:** 10499872
- **Project number:** 1R01CA272863-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Humam Kadara
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $596,247
- **Award type:** 1
- **Project period:** 2022-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499872

## Citation

> US National Institutes of Health, RePORTER application 10499872, Elucidating the evolution of Krt8+ alveolar cells to Kras-mutant lung preneoplasia and cancer (1R01CA272863-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10499872. Licensed CC0.

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