# Phenotype Interactions and Dynamics in SCLC Tumors

> **NIH NIH U54** · VANDERBILT UNIVERSITY · 2022 · $420,340

## Abstract

PROJECT SUMMARY – PROJECT 2
 Small Cell Lung Carcinoma (SCLC) is an aggressive neuroendocrine subtype of lung cancer. SCLC
patients have a very low 5-year survival, in large part because SCLC tumors can become rapidly resistant to
chemotherapy and radiation therapy and because of a lack of targeted therapies. Emerging evidence supports
the idea that, while SCLC tumors seem homogeneous when examined under a microscope, these tumors
contain a significant level of intra-tumoral heterogeneity. Indeed, recent observations by our group and others
have identified distinct cellular phenotypes in SCLC, including in primary human tumors, in cell lines derived
from human tumors, and in tumors from genetically-engineered mouse models. Importantly, data from our
group as well as from Project 1 investigators indicate that these cellular phenotypes contribute to SCLC
development and potentially response to therapy. The specific goal of this proposal is to elucidate how different
cellular subpopulations within SCLC tumors drive SCLC dynamics, growth, survival, and aggressiveness as an
ecosystem. To accomplish this goal, we will focus on better understanding the nature of SCLC phenotypic
subtypes and how these populations functionally interact with each other and with noncancerous cells in the
tumor microenvironment.
 Specifically, we have previously identified stem-like tumor-propagating cells (TPCs) in SCLC tumors and
found that these cells are neuroendocrine and strongly tumorigenic. We have also characterized cell
populations derived from these TPCs with distinct phenotypes, including non-neuroendocrine subpopulations
that can promote the growth and the spread of the neuroendocrine TPCs. Leveraging these findings as well as
our unique genetic mouse models that allow dissection of SCLC phenotype evolution, we will use a
combination of experimental and mathematical approaches to investigate how these different SCLC cell types
contribute to tumor growth, in relationship with the tumor microenvironment. We will build and use
mathematical modeling to predict key interactions between SCLC subpopulations with distinct phenotypes and
to uncover fragility/intervention points that could be used for treatment. Modeling will also be a key factor
driving experimental design. As part of this design, we will determine how cell-cell interactions in SCLC tumors
affect the division and survival rates of the different subpopulations; we will also determine phenotype
transition rates between different subpopulations to capture SCLC dynamics and plasticity. Finally, we will
elucidate the role of secretory factors released by these SCLC subpopulations in driving survival, growth,
phenotype composition, and metastasis of SCLC tumors. These experiments will elucidate basic mechanisms
of SCLC development and progression and may ultimately lead to novel therapeutic approaches by identifying
key interactions of SCLC subpopulations.

## Key facts

- **NIH application ID:** 10375423
- **Project number:** 5U54CA217450-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Alissa M Weaver
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,340
- **Award type:** 5
- **Project period:** 2018-04-13 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375423

## Citation

> US National Institutes of Health, RePORTER application 10375423, Phenotype Interactions and Dynamics in SCLC Tumors (5U54CA217450-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375423. Licensed CC0.

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