# Dissecting the interplay between aging, genotype and the microenvironment in lung cancer

> **NIH NIH U01** · STANFORD UNIVERSITY · 2024 · $457,145

## Abstract

PROJECT SUMMARY
 Cancer is primarily a disease of the old. While this is due in part to the sequential acquisition of genomic
alterations, aging is also associated with a constellation of changes that could impact tumor initiation and growth.
These “hallmarks of aging” involve diverse pathways that impinge on carcinogenesis and lead to systemic
changes. However, despite the very close association between aging and cancer, or perhaps because of it, very
little is known about how cancer cell-intrinsic, microenvironmental, and systemic age-related changes impact
cancer initiation and growth. Genetically engineered mouse models uniquely enable the introduction of defined
genetic alterations into normal adult cells with defined temporal control. Human lung cancer has been modeled
using genetically engineered mouse models, and these tumors recapitulate many features of early-stage human
lung adenocarcinoma. To increase the scope and precision of in vivo cancer modeling, we integrated
conventional genetically engineered mouse models, CRISPR/Cas9-based somatic genome engineering, and
quantitative genomics with statistical approaches. Tumor barcoding coupled with CRISPR/Cas9-mediated gene
inactivation and high-throughput barcode sequencing (Tuba-seq) enables quantitative analysis of the effects of
large panels of genes on tumor initiation and various facets of autochthonous tumor growth. These models can
thus distinguish the effects of aging from mutational events while affording a level of precision that allows us to
detect differences in tumor suppressor function across age contexts. In Aim 1, we will quantify the interaction
between age and tumor suppressor gene function. Our in vivo experiments will define whether aging increases
or decreases the absolute efficiency of tumor initiation and uncover the impact of aging on the importance of
diverse tumor suppressor genes on tumor initiation and growth. In Aim 2. we will determine how the lung tumor
microenvironment and lung cancer cells themselves change with age. We will elucidate the impact of tumor
genotype on the microenvironment across age and determine whether age-dependent changes in growth are
accompanied by dramatic differences in cancer cell state. In Aim 3, we will disentangle cell-autonomous
differences in tumors developing in young and aged mice from effects on tumor suppressor function driven
specifically by aging of the local tissue and systemic host environments. These experiments will provide insight
into whether age-dependent genotype-specific effects are largely cancer cell-intrinsic or driven by the shifts in
the microenvironment or whole organism environment. By permuting cancer cell age and genotype, as well as
microenvironment and host age, we will gain an unprecedented understanding of the contribution of these factors
to multiple aspects of lung carcinogenesis. Ultimately, these findings could have important implication for cancer
prevention, detection, and treatment.

## Key facts

- **NIH application ID:** 10906752
- **Project number:** 5U01AG077922-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Monte Meier Winslow
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $457,145
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906752

## Citation

> US National Institutes of Health, RePORTER application 10906752, Dissecting the interplay between aging, genotype and the microenvironment in lung cancer (5U01AG077922-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10906752. Licensed CC0.

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