# Elucidating the epigenetic mechanism of melanoma dedifferentiation in response to pro-inflammatory cytokines

> **NIH NIH F30** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $50,520

## Abstract

PROJECT SUMMARY/ ABSTRACT
The advent of cancer immunotherapy has remarkably altered the treatment landscape for patients with
advanced melanoma, a highly aggressive skin cancer with traditionally dismal survival outcomes. Despite
notable success of immunotherapy and many studies aimed at improving these therapeutic strategies, a large
proportion of patients fail to respond or develop resistance that leads to relapse. One of the ways melanoma
can adapt to immune attack is through the phenomenon of dedifferentiation, whereby the tumor cell loses
melanoma-specific antigens and upregulates neural crest markers. This altered phenotype has been studied in
mouse models of immunotherapy and in vitro models of targeted therapy, and it has also been linked to
invasiveness and epithelial-to-mesenchymal transition. Notably, we have identified cases of dedifferentiation in
our clinical data from the biopsies of patients who failed to respond to immunotherapy. However, the molecular
mechanism underlying the dedifferentiation provoked by tumor necrosis factor alpha (TNFa) or long-term
interferon gamma (IFNg), two major T cell cytokines, has not been thoroughly explored despite the current gap
in our knowledge. We hypothesize that IFNg and TNFa drive alteration of the global chromatin landscape
to induce differentiation programs that shift the melanoma cell identity, and that the transcription
factor IRF8 is the driver of this observed phenotypic plasticity. We propose to study these hypotheses by
recapitulating dedifferentiation in human melanoma cell lines in vitro. To determine the direction of shift in cell
state, we will investigate the changes in the epigenetic landscape using ATAC-seq. We will also perform RNA-
seq and employ various bioinformatic analysis methods to identify the melanoma-specific immune-driven gene
signature. Furthermore, based on our preliminary data, we propose to test IRF8's role in driving
dedifferentiation by using the CRISPR/Cas9 technology. Finally, we will elucidate whether the altered
melanoma state confers resistance to further T cell attack by performing co-culture experiments with live cell
imaging. These studies will improve our understanding of the mechanism of immune-driven phenotypic
alteration in melanoma and suggest potential ways to circumvent this mode of resistance to immunotherapy.

## Key facts

- **NIH application ID:** 9987264
- **Project number:** 5F30CA243248-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Yeon Joo Kim
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987264

## Citation

> US National Institutes of Health, RePORTER application 9987264, Elucidating the epigenetic mechanism of melanoma dedifferentiation in response to pro-inflammatory cytokines (5F30CA243248-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9987264. Licensed CC0.

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