# Phenotype Heterogeneity and Dynamics in SCLC

> **NIH NIH U54** · VANDERBILT UNIVERSITY · 2020 · $1,732,985

## Abstract

Heterogeneity is a pervasive feature of cancer, central to progression and therapy failure. Both genetic and
nongenetic factors, cell-cell and cell-microenvironment interactions contribute to tumor cell phenotypic variation.
Thus, heterogeneity is a complex multiscale problem difficult to study by reductionist approaches but well
suited to systems thinking. A mechanistic, system-level understanding of heterogeneity would spawn
fundamental advances in cancer treatment strategies. Major challenges include definition of relevant tumor cell
phenotypes, phenotype dynamics emergence from single-cell behavior and interactions, and effective targeting
strategies. In our Center, we will use systems biology approaches to tackle these challenges, focusing on
small cell lung cancer (SCLC), in which the impact of intratumor heterogeneity is particularly compelling. Thus,
SCLC tumors, while histo-pathologically homogeneous with classic “small blue round cell” morphology, are
comprised of phenotypic subpopulations (e.g., tumor-propagating cells; Hes1+ cells; CD44+ cells) that
cooperate to form a tumor ecosystem adaptive to drug treatment. In SCLC genetically engineered mouse
models (GEMMs) and patient tumors, accumulated genetic alterations (e.g., MYC amplification, NOTCH
mutations) may bias phenotypic compositions and consequent drug sensitivity, underscoring the combined role
of genetic and nongenetic sources. The overall goal of our proposed Center is a system-level understanding of
the impact of SCLC phenotype heterogeneity in drug evasion, that will open avenues to novel treatment
strategies. In two highly integrated Projects, we will combine experimentation with mathematical modeling to
generate a comprehensive blueprint of SCLC phenotypic space and identify complex phenotype dynamics
underlying treatment resistance. Project 1 will use high-dimensional cytometry and transcriptomics data to
define human and GEMM core SCLC phenotypes, their susceptibility to genomic alteration bias, and their drug
response plasticity. Project 2 will study SCLC phenotype dynamics initiated by cell-cell and secreted factors or
exosomes in SCLC tumor ecosystems, using models of cell population dynamics driving tumor aggressiveness.
Projects will be supported by a Single-Cell Biology and Data Analysis Shared Resource equipped with a vast
palette of state-of-the-art single-cell technologies, including mass cytometry, scRNA-Seq and multidimensional
data analysis. The Center will be located at Vanderbilt University and a satellite site at Stanford contributing
highly-regarded SCLC GEMMs. Experimental systems will encompass human and GEMM SCLC cell lines and
tumors. Our Center investigators have a track record of co-authored publications in SCLC and/or systems
biology. The Administrative Core will provide leadership and communication across the Center while the
Outreach Core will promote collaborations and disseminate knowledge and tools on SCLC and cancer
heterogeneity. We expect ...

## Key facts

- **NIH application ID:** 9901484
- **Project number:** 5U54CA217450-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Vito Quaranta
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,732,985
- **Award type:** 5
- **Project period:** 2018-04-13 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901484

## Citation

> US National Institutes of Health, RePORTER application 9901484, Phenotype Heterogeneity and Dynamics in SCLC (5U54CA217450-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9901484. Licensed CC0.

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