# Investigating cells of origin and oncogenic modifiers of 3q26-driven LUSC

> **NIH NIH R01** · MAYO CLINIC  JACKSONVILLE · 2022 · $73,693

## Abstract

Project Abstract
Lung squamous cell carcinoma (LUSC) is a major subtype of lung cancer accounting for ~30% of all lung
cancer diagnoses. LUSC patients suffer from poor therapeutic response, high relapse rate, and poor
prognosis. A major reason for this bleak outcome is a lack of well characterized oncogenic drivers of LUSC
that can be targeted therapeutically. We have identified concomitant 3q26 copy number gain (CNG) and
TP53 loss as defining genetic alterations present in ~90% of LUSC tumors.2 Furthermore, we have identified 3
3q26 oncogenes, PRKCI, ECT2 and SOX2, that genetically and biochemically collaborate to drive LUSC tumor
formation.2-4 We have developed the first genetically engineered mouse model (GEMM) to study these genetic
alterations in LUSC tumorigenesis in vivo.1 Our GEMM allows inducible overexpression of Prkci, Ect2, and
Sox2 and knockout of Trp53 (PES/Trp53-/-) in lung tissue. Specific Aims of the parent grant are to: 1) evaluate
the effect of pharmacologic inhibitors of PKCι (the protein product of PRKCI) and PKCι effector pathways on
PES/Trp53-/--driven LUSC; and 2) characterize tumor initiation and progression in our PES/Trp53-/- LUSC
GEMM from lung basal stem cells (LBSCs), a major cell of origin for LUSC. Interestingly, two other regional
lung stem cells (Club and alveolar type II (AT2) cells) can also serve as cells of origin for LUSC.5-7 Moreover,
we have identified additional genes within the recurrent 3q26 amplicon that may play promotive roles in
PES/Trp53-/--driven LUSC. Based on these new observations, we hypothesize that: 1) PES/Trp53-/- mice can
develop LUSC tumors from multiple cells of origin, giving rise to LUSC tumors with distinct biological,
genomic and biochemical properties; and 2) additional genes within the 3q26 amplicon contribute to
PES/Trp53-/--driven LUSC. These hypotheses will be tested through two interrelated specific aims designed
to: 1) To assess the ability of PES/Trp53-/- mice to generate LUSC tumors from Club and AT2 cells in vivo; and
2) determine genomic and molecular signatures of PES/Trp53-/--driven LUSC tumors from distinct cells of
origin. This supplement project is a significant extension of Aim 2 of the parent grant which proposes to
characterize a novel GEMM of PES/Trp53-/--driven LUSC from LBSCs. The proposed studies will expand the
parent grant by: 1) assessing the role of alternative cells of origin (Club and AT2 lung stem cells) in LUSC
tumor formation; 2) identifying genomic and molecular signatures of LUSC tumors arising from LBSC, Club,
and AT2 lung stem cells; and 3) characterizing the role of recently identified 3q26 genes as possible modifiers
of LUSC tumorigenesis. Completion of these studies will provide novel insights into biological heterogeneity
observed in LUSC tumors harboring 3q26 CNG and identify oncogenic signaling pathways and genes that may
be useful as biomarkers of LUSC tumorigenesis and serve as targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10593501
- **Project number:** 3R01CA239726-02S1
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** Alan P. Fields
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $73,693
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593501

## Citation

> US National Institutes of Health, RePORTER application 10593501, Investigating cells of origin and oncogenic modifiers of 3q26-driven LUSC (3R01CA239726-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10593501. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*