# Functions of the LKB1 tumor suppressor in control in metabolism and epigentics

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $62,951

## Abstract

ABSTRACT
Inactivating mutations in the LKB1/STK11 tumor suppressor are found across multiple epithelial tumor
types including ~20% of non-small cell lung cancers (NSCLC) and ~5% of pancreatic ductal
adenocarcinomas (PDA). In NSCLC, these mutations correlate with poor response to conventional,
targeted, and immune-modulating treatment. In pancreatic tumorigenesis, LKB1 mutations are found in
both in premalignant intraductal papillary mucinous neoplasms (IPMN) and in PDA and also portend a poor
prognosis (Furukawa et al., 2007; Yang et al., 2015). Work from our group and others has shown that
LKB1 is a central regulator of cell metabolism (Gurumurthy et al., 2009, Kottakis, et al., 2016). LKB1 loss
results potentiates biosynthetic processes while reducing mitochondrial oxidative phosphorylation. The
basis for metabolic reprogramming in LKB1 mutant cells is incompletely understood. This proposal seeks
to explore the novel roles of LKB1 in the regulation of the mitochondria. Our preliminary data indicate that
mitochondrial dysfunction is central to the pathogenesis of LKB1 mutant tumors and presents significant
new therapeutic vulnerabilities. In preliminary studies, we find that LKB1 mutant (LKB1m) cancer cells
exhibit a striking change in mitochondrial architecture and that LKB1 directly controls two fundamental
processes of mitochondrial homeostasis—maintaining the balance between mitochondrial fusion and
fission and activating the primary mechanism for repair or clearance of damaged mitochondria. These
findings have important functional implications. Our preliminary studies indicate that restoration of
mitochondrial fusion is lethal in LKB1m cancer cells; that these cells are hypersensitive to mitochondrial
insults; and that defective mitochondrial quality control can be further exploited to restore anti-tumor
immunity. The overarching concept emerging from these studies is these specific mitochondrial alterations
are a hallmark of LKB1 mutant NSCLC and PDA, and that deciphering the mechanisms of mitochondrial
regulation will open new therapeutic directions.
The present proposal focuses one aspect of these mitochondrial phenotypes, the increase in mitochondrial
fission resulting from LKB1 loss. Mitochondrial dynamics, the conversion between fusion and fission,
configure mitochondria between tubular and fragmentated states, which have distinct metabolic outputs.
Fusion leads to tightly packed cristae, efficient OXPHOS and fatty acid oxidation, whereas fission expands
the cristae, reduces OXPHOS efficiency and promotes aerobic glycolysis. Our proposed studies will test
the hypothesis that mitochondrial hyper-fragmentation resulting from LKB1 loss drives metabolic
reprogramming essential for tumorigenesis. To this end, we will modulate mitochondrial dynamics using
genetic and pharmacological approaches in novel in vitro and in vivo model systems, and we will test the
resulting impact on metabolic homeostasis and tumor cell growth and survival. Resul...

## Key facts

- **NIH application ID:** 10026739
- **Project number:** 3R01CA215498-03S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $62,951
- **Award type:** 3
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026739

## Citation

> US National Institutes of Health, RePORTER application 10026739, Functions of the LKB1 tumor suppressor in control in metabolism and epigentics (3R01CA215498-03S1). Retrieved via AI Analytics 2026-07-24 from https://api.ai-analytics.org/grant/nih/10026739. Licensed CC0.

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