# NANOG-positive cancer stem cells in liver oncogenesis induced by alcohol and HCV

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $371,250

## Abstract

Abstract: Deaths due to metastatic hepatocellular carcinoma (HCC) continue to mount due to a low success of
clinical intervention. Targeted cancer therapy eliminates all malignant tumor-initiating stem-like cells (
TICs) to
prevent relapse and metastasis. Development of HCC is associated with alcohol and/or HCV infection and
frequently observed in patients with gene aberrations in component
complex SWI/SNF. Our synthetic lethal gene screening of genome-wide CRISPR-based knockout
(GeCKO)-lentivirus library in ARID1A-mutant cells of our humanized mouse models identified components
(EZH2 and EED) of polycomb suppressor complex 2 (PRC2). We demonstrated that pluripotency transcription
factor NANOG metabolically reprograms TICs to promote self-renewal via inhibition of oxidative
phosphorylation (OXPHOS) and activation of fatty acid oxidation (FAO). We characterized alcohol-associated
human HCCs and alcohol-fed, HCV NS5A transgenic (Tg) mice for HCC development and a critical role of
NANOG as a core stem cell factor following TLR4 activation as a crucial component needed for genesis and
maintenance of TICs.
 These findings support our hypothesis that alcohol-mediated NANOG induction and ARID1A mutations
cooperatively generate chemoresistant TICs in alcohol-associated HCC. Therefore, targeting
ARID1A, a
of chromatin remodeling
NANOG-PRC2 complex and FAO should eliminate the TIC subpopulation. We propose three specific aims. In
Aim 1, we will test if NANOG with PRC2 complex inhibits OXPHOS and generates sorafenib-resistant TICs with
mutant ARID1A in alcohol mediated human HCCs. In Aim 2, we will examine how inhibition of FAO inhibit
self-renewal and promote apoprtosis in sorafenib-resistant mutant ARID1A tumors. In Aim 3, we will test if
combination therapy of sorafenib plus PRC2/FAO inhibition induces metabolic reprogramming and apoptosis in
HCC. We will test if targeting synthetic lethality genes (EZH2) eliminates TICs with ARID1A mutations by use of
alcohol Western diet-fed and/or HCV-infected FRG-hu-Hep/HSC humanized mice and patient-derived
xenograft.
 In summary our genotyped HCC model will streamline clinical trials for disease modeling/toxicity evaluation
by offering “a clinical trial in a humanized mouse”. Use of PDX and humanized mouse systems will provide a
path to paradigm-shifting personalized medicine for an accurate synthetic lethality targeting strategy. The timely
eradication of chemoresistant TICs arising from chronic alcohol exposure will be
beneficial and cost-effective for
patients suffering from an otherwise incurable disease.
This proposal will establish a personalized therapy
strategy targeting a synthetic lethal pathway (PRC2)-NANOG complex and FAO in mutant-ARID1A HCCs. A
successful outcome will lead to a paradigm shift, thus facilitating the future development of personalized
treatment strategies targeted towards NANOG+ TICs appearing in alcohol-related HCC.

## Key facts

- **NIH application ID:** 9941006
- **Project number:** 5R01AA025204-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Keigo Machida
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941006

## Citation

> US National Institutes of Health, RePORTER application 9941006, NANOG-positive cancer stem cells in liver oncogenesis induced by alcohol and HCV (5R01AA025204-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9941006. Licensed CC0.

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