# Lineage heterogeneity and plasticity in lung cancer

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $502,376

## Abstract

PROJECT SUMMARY
Large-scale genomic studies have discovered numerous relevant alterations that activate or inactivate key
signaling molecules in lung cancer, which led to significant improvement on patients' outcome and our
therapeutic options. Despite these advances in the genome-based precision medicine, the 5-year survival rate
of 18% remains less than adequate. This is attributable to eventual emergence of resistance and variability in
response to the treatment, largely due to heterogeneity of lung cancers. To improve precision and efficacy,
innovative strategies to distinguish different subgroups of lung cancer by additional features for future drug
development are desperately needed. We hypothesize that our natural system to populate necessary cells to
constitute the organ structure and its function is hijacked by cancer mimicking normal cell identities to maintain
their survival. Our previous studies found lung cancer cells harboring amplification of lineage oncogenes are
specifically dependent on their expression for survival. The need for lineage amplified genes in a subset of
cancers suggests unique vulnerabilities in cancer cells that may be poised at the brink of survival. However,
these amplifications represent only a minor subset of the two major subtypes of lung cancers. Therefore, this
study will focus on lineage factors essential during the development and control the cell identity in adult, in the
remaining subsets of lung cancers. Through genome-wide profiling of a histone mark, we identified `super-
enhancers' (SE) on the lineage-defining transcription factor genes. Subsequent hierarchical clustering of lung
cancer samples identified SEs specific to subsets of lung cancers. Therefore, we aim to understand the
significance of our lead candidates defining the lineage state of the novel subsets in aim 1. We will test the
subclass-specific local chromatin structure and then investigate the roles of novel lineage transcription factors
specifically enriched in the two major subgroups of lung ADCs, whether they are essential for maintaining the
cellular state of lung cancer cells and are dependent on the committed lineage for their survival. In aim 2, to
determine the roles of a neural transcription factor Brn2 in a novel `neural' subtype of lung squamous cell
cancers (SCC) as a cooperative partner of Sox2, by contrast to p63, a key squamous lineage factor we
previously characterized as an important cooperative partner of Sox2 in classic lung SCC. In aim 3, to pursue
inducing transdifferentiation as a therapeutic strategy, we seek to understand how lineage switch occurs within
a tumor by determining heterogeneity and dynamics of lineage states. We will determine the mode of temporal
dynamics of population shifts in lineage states induced by genetic perturbation in defined models via profiling
genome-wide chromatin landscapes at a single cell level. We will then test our hypothesis that the degree of
heterogeneity correlates with plas...

## Key facts

- **NIH application ID:** 10223240
- **Project number:** 5R01CA240342-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Hideo Watanabe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $502,376
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223240

## Citation

> US National Institutes of Health, RePORTER application 10223240, Lineage heterogeneity and plasticity in lung cancer (5R01CA240342-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10223240. Licensed CC0.

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