# Single-Cell RNA Sequencing of Cardiac Organoids to Determine the Genetic Basis for Cell-Specific Responses to Anticancer Drugs

> **NIH NIH F31** · UNIVERSITY OF CHICAGO · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Anticancer drug-induced cardiovascular toxicity (CT) is a major side effect for many patients undergoing
treatment for oncological disorders. CT symptoms vary widely across individuals, both in presentation and in
time to onset. Risk of CT complicates treatment protocols and places cancer patients under additional duress.
Genetic background is broadly understood to be a component of CT susceptibility, but specific variants and
mechanisms remain largely unknown. To understand the genetic basis for drug-induced CT, we need to
understand how anticancer drugs stimulate transcriptomic responses in multiple cardiovascular cell types from
individuals of different genetic backgrounds. Inter-individual variability in response to anticancer drugs is
mediated by genetic variants that affect gene regulation in a drug-dependent manner (response eQTLs). In
other words, genetic variants respond to anticancer drugs by regulating the activity of specific genes. Notably,
different cell types can vary in their response eQTLs to anticancer drugs. I propose to determine the genetic
basis for transcriptomic responses to the anticancer drugs doxorubicin (DOX), 5-fluorouracil (5-FU), and
bevacizumab (BVC) in multiple cardiac cell types from a genetically diverse panel of 70 individuals.
Identification of CT-associated response eQTLs necessitates a high-throughput model system comprised of
multiple cardiac cell types. For Aim 1 of my proposal, I have developed a culture environment and guided
differentiation protocol conducive to cardiac lineage and supporting cell types. This procedure reproducibly
transforms induced pluripotent stem cell (iPSC)-derived embryoid bodies (EBs) into cardiac organoids.
Preliminary data demonstrate that the cardiac organoids harbor cardiomyocytes, fibroblasts, vascular
endothelial cells, and other mesodermal cell types. In Aim 2, I will perform single-cell RNA sequencing
(scRNA-seq) on a panel of 70 cardiac organoids cultured in control and drug-treated conditions. Repeating
this experiment across multiple individuals will allow me to identify the response eQTLs that regulate how
different cardiovascular cell types respond to each drug. In Aim 3, I will quantify gene expression levels and
identify response eQTLs that regulate transcriptional changes to each anticancer drug in cardiovascular cell
types. Response eQTLs (which are anchored by genotype) provide a catalog of loci that interact either directly
or indirectly with the treatment. These response eQTLs may reveal specific genes and pathways important for
normal cardiovascular function. Elucidating the genetic architecture underlying CT risk will provide intuition on
cardiotoxic mechanisms and associated genes and inform future studies that aim to classify individual patient
susceptibility.

## Key facts

- **NIH application ID:** 11062344
- **Project number:** 5F31HL168912-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Erik McIntire
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11062344

## Citation

> US National Institutes of Health, RePORTER application 11062344, Single-Cell RNA Sequencing of Cardiac Organoids to Determine the Genetic Basis for Cell-Specific Responses to Anticancer Drugs (5F31HL168912-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11062344. Licensed CC0.

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