# Transcriptional Reprogramming in Melanoma Plasticity

> **NIH NIH R01** · WISTAR INSTITUTE · 2024 · $614,911

## Abstract

Project Summary/Abstract
This application focuses on advanced melanoma, a highly aggressive type of skin cancer that arises from the
pigment-producing melanocytes of the body. Despite recent advances in molecularly targeted therapy and
immunotherapeutic agents with impressive response rates, there remain patients who either do not respond to
such therapies or who eventually relapse. The 5-year overall survival rate for metastatic melanoma is below
20%. Progressive dedifferentiation and phenotypic switching of melanoma cells under cellular stress are
considered to be a major driver for both tumor progression and therapy resistance. However, the molecular
mechanisms that govern this process, and their interplay with genetic lesions and the tumor microenvironment
are poorly understood. TFEB is a member of the MiT/TFE family of transcription factors and master regulators
of cell differentiation pathways. Our preliminary studies identified TFEB repression as a novel dependency of
oncogene-driven melanoma progression. We showed that TFEB activation globally re-invigorates
transcriptional differentiation of melanocytes, while its inactivation provokes phenotypic transition towards the
invasive and drug-resistant states that is associated with aberrant TGF-b upregulation. Furthermore,
transcriptomic and immune cell profiling of tumors from primary melanoma patients confirmed dampened
TFEB expression and function that also correlates with tumors’ immune evasive microenvironment. These
findings lead us to hypothesize that TFEB-mediated transcriptional reprogramming of melanoma cell
differentiation states represents a key mechanism disabling melanoma progression, which also
reshapes tumor immune microenvironment for enhanced anti-tumor immunity. We will test the
hypothesis by (Aim 1) defining the molecular mechanisms of TFEB-mediated transcriptional reprogramming of
melanoma cell plasticity and phenotype switching; and by (Aim 2) investigating in detail the in vivo impact of
TFEB alteration in melanoma progression and immune evasion. Successful completion of this study will
provide mechanistic insights into tumor cell-switching processes and hold promise for the development of
novel therapeutic strategies to reverse this process for the prevention and elimination of tumor metastasis and
recurrence.

## Key facts

- **NIH application ID:** 10858175
- **Project number:** 1R01CA289624-01
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Chengyu Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $614,911
- **Award type:** 1
- **Project period:** 2024-07-18 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10858175

## Citation

> US National Institutes of Health, RePORTER application 10858175, Transcriptional Reprogramming in Melanoma Plasticity (1R01CA289624-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10858175. Licensed CC0.

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