# Interplay between host microbiome and immunomodulatory responses in the pathogenesis of Kras mutant lung cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $532,609

## Abstract

PROJECT SUMMARY
Lung adenocarcinoma (LUAD) is the most common cancer diagnosed in lifetime smokers of whom there are
more than 90 million in the United States. Smokers with LUAD frequently (more than 25%) harbor somatic
activating mutations in the Kras oncogene. Kras-mutant LUAD (KM-LUAD) displays very poor clinical outcome
and inferior response to therapy. Despite the urgent need of new strategies for early treatment of this fatal
disease, we still do not understand targetable changes that promote onset of KM-LUAD. Using a human-
relevant genetically engineered mouse model comprised of tobacco exposure and high somatic mutation
burdens including driver Kras variants, features that constitute a perfect storm for LUAD pathogenesis in
humans, we identified significant progressive changes in gut microbiome composition that were coexistent with
reduced levels of gut and circulating bacterial metabolites and closely associated with evolution of KM-LUAD.
Similar microbial phenotypes were observed in mice exposed to combustible cigarette smoke (CCS). We
further found in lungs of the mice up-regulation of pro-tumor inflammatory cues including activation of the IL-6
/STAT3 pathway which we have previously shown to promote KM-LUAD development by immune
reprogramming. Also, we noted that lipocalin 2 (LCN2), a host defense antimicrobial protein that is released
from cells during microbiome imbalance, was markedly progressively up-regulated in normal airway cells prior
to onset of Kras-mutant preneoplasias and LUADs. Genetic deletion of Lcn2 in these mice markedly increased
KM-LUAD development concomitant with global changes in the gut microbiome and heightened pro-tumor lung
inflammation. Despite these insights, the interplay between the host microbiome and key immune responses in
the pathogenesis of KM-LUAD are poorly understood. We hypothesize that the host microbiome (derived
from the gut and possibly the lung) promotes tobacco-associated KM-LUAD development through
activation of the IL-6/STAT3 pathway and changes in systemic and lung immune contexture. We will
address our hypothesis using the following three aims. In Aim 1, using sequencing, metagenomics, as well as
bacterial metabolite and immune profiling approaches, we will discern evolving microbiome changes that are
functionally linked to tobacco carcinogen- and CCS-associated KM-LUAD development as well as probe
downstream systemic and local (in lung) immunomodulatory effects including those on the pro-tumor IL-
6/STAT3 pathway. In Aim 2, we will determine the role of host antimicrobial and immunomodulatory cues
mediated by LCN2 induction in KM-LUAD pathogenesis. In Aim 3, we will investigate chemopreventive and
early therapeutic effects of microbiome intervention, alone or in combination with immunotherapy, against KM-
LUAD. At the conclusion of our studies, we will have shed light on uncharted host processes in the evolution of
KM-LUAD, paved the way for identification of new targets to guide che...

## Key facts

- **NIH application ID:** 10769732
- **Project number:** 5R01CA248731-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Humam Kadara
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $532,609
- **Award type:** 5
- **Project period:** 2021-02-19 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769732

## Citation

> US National Institutes of Health, RePORTER application 10769732, Interplay between host microbiome and immunomodulatory responses in the pathogenesis of Kras mutant lung cancer (5R01CA248731-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10769732. Licensed CC0.

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