# Three-Dimensional Organoid Cultures to Investigate 3q26 Driver Functions in Multiple Lung Cancer Cells of Origin

> **NIH NIH R01** · MAYO CLINIC  JACKSONVILLE · 2020 · $53,210

## Abstract

SUPPLEMENT PROJECT SUMMARY
Lung squamous cell carcinoma (LSCC) is a major sub-type of lung cancer. LSCC tumors can be further sub-
classified into four distinct molecular subtypes: primitive, classical, secretory and basal based on expression
profiling. The LSCC molecular subtypes share similarities in gene expression profiles with distinct lung
epithelial cell populations suggesting that the LSCC molecular subtypes may originate from different lung
epithelial cell populations. Genomic analysis of human LSCC pre-neoplastic lesions and tumors demonstrates
that 3q26 copy number gains (CNGs) and TP53 mutations are among the most prevalent early genetic
alterations in LSCC, suggesting that these genetic events play an important role in the initiation and
progression of LSCC. Furthermore, interrogation of The Cancer Genome Atlas (TCGA) LSCC database
reveals that 3q26 CNGs are present in all four LSCC molecular subtypes suggesting that 3q26 CNGs may play
a role in the molecular signaling pathways that drive the pathogenesis of these molecular subtypes. Our
studies have shown that the genes SOX2, PRKCI and ECT2 are key targets of 3q26 CNGs that functionally
collaborate in maintaining the transformed phenotype of human LSCC cells. Our more recent studies have
demonstrated that overexpression of SOX2, PRKCI and ECT2, in the context of Trp53 loss, is sufficient to; 1)
transform mouse lung basal stem cells (LBSCs) (a cell of origin for LSCC); and 2) drive formation of LBSC
tumors with LSCC-like histopathology in vivo. Based on these observations, we hypothesize that co-
overexpression of SOX2, PRKCI and ECT2 and Trp53 loss can cooperate to transform other putative LSCC
cells of origin to develop LSCC-like tumors that exhibit signaling pathways observed in the four human LSCC
molecular subtypes. This hypothesis will be tested through two interrelated specific aims designed to; 1)
assess cooperative oncogenic activities of SOX2, PRKCI and ECT2 on the transformation of putative LSCC
cells of origin; and 2) determine the mechanisms underlying the roles of SOX2, PRKCI and ECT2 in lung
epithelial cell transformation and LSCC development. Successful completion of these aims will provide
important mechanistic insight into the molecular heterogeneity of LSCC and offer novel pre-clinical models to
identify and evaluate therapeutic targets in distinct molecular subtypes of LSCC.

## Key facts

- **NIH application ID:** 10134075
- **Project number:** 3R01CA081436-23S1
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Alan P. Fields
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $53,210
- **Award type:** 3
- **Project period:** 1999-04-02 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134075

## Citation

> US National Institutes of Health, RePORTER application 10134075, Three-Dimensional Organoid Cultures to Investigate 3q26 Driver Functions in Multiple Lung Cancer Cells of Origin (3R01CA081436-23S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134075. Licensed CC0.

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