# Molecular dissection of Lkb1-mediated tumor suppression

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $409,805

## Abstract

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PROJECT SUMMARY
Lung cancer is the leading cause of cancer deaths in both men and women in the United States, with over
155,000 patients dying each year in this country alone. Cancer genome sequencing has begun to uncover the
compendium of mutations within human lung adenocarcinoma, but despite these advances we still have a very
limited understanding of the molecular and cellular mechanisms by which even the most frequently mutated
genes drive cancer growth. In particular, the molecular and cellular consequences of tumor suppressor gene
function have been difficult to understand, slowing our understanding of these pathways and stalling
personalized oncology approaches aimed at tailoring therapies based on tumor suppressor genotypes. In this
proposal, we will employ several innovative methods to uncover the mechanisms by which the Lkb1 tumor
suppression constrains lung cancer growth. This will enable a detailed understanding of the tumor suppressive
function of Lkb1. While current tools have led to important insights into tumor biology, the inability to restore
tumor-suppressor genes of interest at will in established tumors in vivo, has hampered our understanding of
their molecular and cellular functions. We have generated mice with a conditionally-inactivable and
conditionally-restorable genetic system which allows Lkb1 inactivation and subsequent restoration in
autochthonous tumors. To characterize Lkb1-mediated tumor suppression, we will use this allele system to
restore Lkb1 expression in lung tumors in vivo. Cellular and molecular analysis both in cell culture and in vivo
will extend preliminary findings which linkLkb1 to changes in chromatin accessibility. To further understand the
impact of the chromatin landscape on Lkb1-mediated tumor suppression, we will perform cell culture and in
vivo experiments focused on the epistatic relationship between Lkb1 and epigenetic modifying enzymes
identified in a genome-scale screen for suppressors of Lkb1-mediated growth suppression. Finally, we will
investigate the relative importance of the Sik family of kinases which we have found to be tumor suppressive
Lkb1-substrates. Our overall goals are to understand the molecular and cellular responses of lung tumors to
Lkb1/Sik-mediated tumor suppression as well as to uncover how this response is related to changes in
chromatin state. Our preliminary data, novel genetic systems, and strong collaborative team make us uniquely
positioned to conduct these studies. Our proposed research is significant because it will increase our
fundamental understanding of how Lkb1 limits lung tumor growth, illuminate the connection between Lkb1 and
chromatin state dynamics, and potentially uncover novel and therapeutically targetable pro-tumorigenic
pathways.
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## Key facts

- **NIH application ID:** 10405647
- **Project number:** 5R01CA230919-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Monte Meier Winslow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,805
- **Award type:** 5
- **Project period:** 2018-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405647

## Citation

> US National Institutes of Health, RePORTER application 10405647, Molecular dissection of Lkb1-mediated tumor suppression (5R01CA230919-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10405647. Licensed CC0.

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