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Targeted intervention of melanoma by reprogramming the stromal translatome

Yangpeiwei Huang, PhD

Mentor Davide Ruggero, PhD
Award Type Career Development Award
Institution University of California, San Francisco
Donor Support Generously funded by the Silverstein Family Research Challenge Grant

Gender is an important factor in patients with melanoma. Female melanoma patients have an advantage over their male counterparts in terms of survival. However, the reason for the gender disparity in melanoma prognosis is poorly understood. Sex is an important variable in tumor pathogenesis and therapy responses; but there are few reports describing potential sex-based differences in potential sex-based differential responses to tumor therapy. The lack of sex-based differences in study design led to the failure to analyze differences in drug efficacy and side-effect profiles. Therefore, deciphering the gender differences in melanoma will benefit the design of sex-based therapeutic regimens.

Melanomas are composed of a repertoire of non-tumor cells, such as immune cells, fibroblasts and endothelial cells, which co-evolve with tumor cells and contribute to tumor development. The stromal cells sensitively respond to changes in the tumor microenvironment (TME) during malignant transformation and therefore require rapid adaptations in gene expression, which relies on the efficient protein synthesis. Interestingly, I found that the key translation initiation factor, eIF4E, might be the missing link between translational remodeling of the TME and environmental factors driving melanoma sex disparities.

The goal of this proposal is to characterize eIF4E-mediated sex-related differences in melanoma progression and test the therapeutic potential of targeting eIF4E in both genders. In my preliminary studies, I have obtained evidence that immune microenvironment is drastically influenced by eIF4E dose in female mice but not in males, suggesting that eIF4E is essential for suppressing anti-tumor immunity in females. In this proposal, I will define eIF4E dose-mediated gender-dependent alterations of immune microenvironment and how they influence melanoma progression. I will further identify eIF4E-dosage-sensitive mRNAs that are critical for immune cell function. Lastly, I will investigate whether female patients achieve better therapeutic responses to eIF4E inhibitor.

These studies will establish the first functional link between protein synthesis control and gender disparities in cancer. This proposal will uncover novel subsets of transcripts that are regulated by key translation factors in immune cells, thereby providing a completely new metric for understanding and predicting which bursts of gene expression propagated by translational control drive tumor development. With anticancer agents targeting eIF4E currently in clinical trials and available in our lab, this study holds great promise for treating human cancer by modulating the TME proteome.