# Role of EPAC Signaling in Melanoma Progression

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2022 · —

## Abstract

ABSTRACT
Cutaneous melanoma arises from melanocytes in the skin. Exposure to solar ultraviolet (UV) radiation is a
significant risk factor. Deployment of US military personnel around the world in areas of high UV index thus
increases risk of melanoma during and after military service. If diagnosed early, excision of the primary tumor in
the skin can be curative. However, the five-year survival rates decrease precipitously as melanoma metastasizes
to local and regional lymph nodes and distant organs. Despite the recent successes and promise of targeted
therapies and immunotherapy, early diagnosis and treatment of the localized primary cancer remain the best
strategies to reduce cancer mortality. Therefore, a detailed understanding of the molecular mechanisms involved
in melanoma tumor progression is critical for accurate and reliable diagnosis and treatment of aggressive
cutaneous melanoma. Cyclic AMP (cAMP) signaling pathway plays a critical role in melanocyte proliferation and
differentiation. This pathway is initiated upon elevation of intracellular cAMP by the catalytic activity of adenylyl
cyclases and transduced through protein kinase A and transcription factor CREB culminating in expression of
cAMP-responsive genes including the melanocyte master regulator, MITF. The role for cAMP signaling pathway
in melanoma is not fully understood. Employing a human primary melanoma tissue microarray (TMA), a panel
primary and metastatic melanoma cell lines and the BrafV600E/Pten-/- mouse model for melanoma, we recently
demonstrated that cAMP signaling plays opposite roles in primary and metastatic melanoma cells, i. e., as a pro-
proliferative signal in primary and as anti-proliferative signal in metastatic cells. We also showed that this switch
in the cAMP of action is mediated by the alternative cAMP signaling axis involving EPAC-RAP1 (Exchange factor
directly activated by cAMP- Ras-related protein 1). Additional studies showed that EPAC promotes cell cycle
progression, activates mTORC1 signaling, and regulates cellular metabolism and mitochondrial ROS production
selectively in primary melanoma cells. Furthermore, studies using a panel of primary and metastatic melanoma
cell lines derived from the same patient revealed that the switch in the functions of EPAC occurs progressively
during melanoma metastasis suggesting that EPAC is a critical component for the growth of primary melanoma
and that rewiring of signaling networks during tumor progression abolish EPAC dependency in metastatic
melanoma. Here, we propose to test the hypotheses that a) oncogenic transformation of melanocytes activates
EPAC signaling and EPAC acts as a critical signaling node to suppress stress induced ROS generation, promote
senescence escape and primary melanoma development, and b) gene expression changes and metabolic
adaptions that occur during metastasis progressively abolish EPAC dependency. The specific aims of this
application are: 1) Establish the role of EPAC in melano...

## Key facts

- **NIH application ID:** 10292971
- **Project number:** 5I01BX004921-03
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Vijayasaradhi Setaluri
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10292971

## Citation

> US National Institutes of Health, RePORTER application 10292971, Role of EPAC Signaling in Melanoma Progression (5I01BX004921-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10292971. Licensed CC0.

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