# Alveolar epithelial cell type 2 populations and single cell gene expressions in non-small cell lung cancer progression and drug resistance

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2024 · —

## Abstract

Non-small cell lung cancer (NSCLC) is by far the leading cancer killer in Veterans. Major reasons for death
after surgical resection are the >50% recurrence rate despite curative intent treatment due to micrometastatic
disease at the time of diagnosis. To prevent the development of metastatic recurrence, surgically treated
patients receive adjuvant chemotherapy to eradicate undetectable micrometastatic disease. However, this
therapy is only associated with a 5% survival benefit due to drug resistances of cancer cells. Identifying
personalized treatment strategies to prevent metastases remains an unmet clinical need. Alveolar epithelial
type II (AT2) cells are self-renewing epithelial stem cells in the lung that have been identified as the origin for a
majority of NSCLCs. However, it is unknown whether and how epithelial cancer cells, such as AT2 cells,
contribute to metastatic progression as the major cause of death. Novel data link AT2 cells to the development
of NSCLC metastases. A research team led by a surgeon scientist has integrated expertise in human
biobanking and translational cancer research at two VA hospitals with collaborators specialized in preclinical
cancer models, single cell sequencing, genetics, and bioinformatics. It will be investigated how AT2 and other
epithelial cancer cells contribute to NSCLC metastatic progression and drug resistances, as this will allow
better molecular targeting to improve cure rates. Micrometastatic cells, such as circulating tumor cells (CTCs),
are surrogates of the early metastatic process that can be detected by a blood draw as a liquid biopsy.
Currently available preclinical models used to study the spectrum of cancer progression from a localized
primary tumor to metastatic disease are limited. To combat this, a library of patient-derived xenograft (PDX)
mouse models using primary tumors, micrometastatic CTCs (CDX) and brain metastases was developed.
Using single cell RNA sequencing techniques, presence of an additional AT2 population was confirmed in
NSCLC patients' metastatic tissues and primary lung tumors that had metastasized already. However, AT2
cells were absent in primary lung tumors of patients that had not metastasized. Importantly, AT2-depleted
NSCLC cell lines have reduced tumorigenicity in PDX mouse models. Gene expression and culture data also
suggest a strong migratory capacity of AT2-like cancer cells. This indicates an important role of AT2 cells in
metastatic progression. For further validation of these critical leads, patient-derived organoid (PDO) pipelines
for high-throughput tumor growth and drug response testing were generated. It is innovative to expand on
metastasis-associated epithelial cancer cells, such as AT2, using patient-derived models and identify drug
targets. Based on the rationale that AT2 populations with an impact on tumorigenicity are identified in
metastases, the hypothesis is that AT2 cells promote NSCLC metastatic progression and express cancer-
relevant...

## Key facts

- **NIH application ID:** 10699520
- **Project number:** 1I01CX002498-01A2
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** Jussuf Thomas Kaifi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10699520

## Citation

> US National Institutes of Health, RePORTER application 10699520, Alveolar epithelial cell type 2 populations and single cell gene expressions in non-small cell lung cancer progression and drug resistance (1I01CX002498-01A2). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10699520. Licensed CC0.

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