Dissertations and Theses (Open Access)

Author ORCID Identifier

SARA SAINANI (0009-0004-3975-6267)

Date of Graduation

8-2026

Document Type

Thesis (MS)

Program Affiliation

Cancer Biology

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Andrea Viale, M.D.

Committee Member

Stephanie S. Watowich, Ph.D.

Committee Member

Yonathan Lissanu, M.D., Ph.D.

Committee Member

Yejing Ge, Ph.D.

Committee Member

Lawrence Kwong, Ph.D.

Abstract

Cutaneous Malignant Melanoma (CMM) is the most aggressive form of skin cancer and arises from the malignant transformation of melanocytes, the pigment-producing cells located in the basal layer of the epidermis. Unlike most epithelial cancers with peak incidence rates at older ages, CMM is among the most common malignancies seen in adolescents and young adults. Although highly curable when diagnosed early, CMM remains a major clinical challenge when the disease disseminates or becomes resistant to immunotherapy. Most melanomas develop on sun-exposed skin, carry Ultraviolet (UV)-associated mutations, and frequently harbor early somatic BRAFV600E alterations. As a result, prevention strategies have largely focused on limiting sun exposure together with routine dermatological screening.

However, recent studies have shown that individual epithelial cells and melanocytes from normal human skin carry a substantial burden of somatic and oncogenic mutations dominated by UV-associated mutational signatures, but most do not progress to cancer. This suggests that additional factors are required for malignant transformation. Interestingly, melanoma mortality is higher in developed countries, regardless of population skin color or genetic predisposition, pointing toward behavioral, lifestyle-related or environmental contributors associated with modern living.

We hypothesize that chemicals present in Body-Care Products (BCPs) may represent one such exposure. Most BCP ingredients are inadequately evaluated for toxicity, yet daily use results in chronic exposure to complex chemical mixtures applied directly to the skin. To address this possibility, we collaborated with the Environmental Working Group (EWG), a non-profit organization, to gain access to their toxicologically annotated database, which includes all chemicals used as ingredients in BCPs commercialized over the past four decades.

We specifically focused on leave-on BCPs applied to different body parts because unlike rinse-off products, they remain on the skin for prolonged periods after application and may therefore result in more sustained cutaneous exposure. Based on this rationale, we built a screening library composed of chemicals commonly found in leave-on BCPs. To explore the cell-intrinsic effects of BCP chemicals on priming melanocytes for transformation by oncogenic BRAF, we conducted a high-throughput chemical screen on human dermal melanocytes engineered to express mutant BRAFV600E upon doxycycline treatment. This system allowed us to identify compounds that enable melanocytes to bypass Oncogene-Induced Senescence (OIS), a critical checkpoint activated in non-transformed melanocytes in response to oncogene activation. In-vitro identified chemicals were also evaluated in-vivo using different mouse models. In parallel, we also examined the cell-extrinsic effects of BCP chemicals on the skin microenvironment, specifically their impact on tissue response and recovery following acute inflammation and damage induced by UVB exposure. Finally, we investigated whether BRAFV600E mutations (found in approximately 50% of melanomas) and UVB exposure can synergize with BCP-derived chemicals to promote early tumor development.

The primary objective of this study is to establish a robust platform to test, identify, and characterize chemicals found in BCPs that may increase melanoma risk. Understanding preventable risk factors can guide early intervention and help build predictive signatures for high-risk melanoma development even in healthy individuals.

Keywords

Melanoma initiation, Body-Care Products (BCPs), Oncogene-induced Senescence (OIS), Inflammation

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Available for download on Monday, January 25, 2027

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