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Background/Aim: The FOXC2 transcription factor promotes the progression of several cancer types, but has not been investigated in the context of melanoma cells. To study FOXC2's influence on melanoma progression, we generated a FOXC2-deficient murine melanoma cell line and evaluated The Cancer Genome Atlas (TCGA) patient datasets. Materials and Methods: We compared tumor growth kinetics and RNA-seq/qRT-PCR gene expression profiles from wild-type versus FOXC2-deficient murine melanomas. We also performed Kaplan-Meier survival analysis of TCGA data to assess the influence of FOXC2 gene expression on melanoma patients' response to chemotherapy and immunotherapy. Results: FOXC2 promotes melanoma progression and regulates the expression of genes associated with multiple oncogenic pathways, including the oxidative stress response, xenobiotic metabolism, and interferon responsiveness. FOXC2 expression in melanoma correlates negatively with patient response to chemotherapy and immunotherapy. Conclusion: FOXC2 drives a tumor-promoting gene expression program in melanoma and is a prognostic indicator of patient response to multiple cancer therapies. Melanoma, a highly aggressive form of cancer arising from pigment-producing melanocytes, is responsible for the majority of skin cancer-related mortality, accounting for~6 0,000 annual deaths worldwide (1). Importantly, the incidence of melanoma has risen substantially over the last 40 years (2), a trend that is expected to continue to at least 2031 (3). Although surgical removal of primary lesions is typically successful in the treatment of early-stage disease, many melanoma patients are not diagnosed until later stages of metastatic disease in which surgery is either not possible or largely ineffective. Unfortunately, malignant melanoma is highly resistant to radiation and chemotherapy, and the only FDA-approved chemotherapeutic for the treatment of melanoma, dacarbazine (DTIC), has a minimal impact on patient survival (4). While advances in targeted therapy and immunotherapy have improved the prognosis for melanoma in recent years, there are still patients who do not respond to these regimens, and relapse of therapy-resistant tumors remains an ongoing challenge in many patients who do achieve clinical benefit (5, 6). Therefore, in order to improve the clinical outcome of melanoma patients going forward, it is necessary to gain additional insight into factors that promote melanoma progression and resistance to these therapeutic modalities. FOXC2 is a member of the forkhead box family of transcription factors that control a variety of cellular processes in embryonic and adult tissues. In addition to its normal regulation of development, growth, and metabolism in various tissue types, FOXC2 has recently emerged as a driver of several hallmarks of cancer progression as well. Within vascular endothelial cells, FOXC2 promotes expression of multiple genes that enhance angiogenesis (7-9). FOXC2 can also become overexpressed or dysregulated in tumor cells themselves, where it is asso...

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The FOXC2 transcription factor has emerged as a tumor-promoting oncogene in many cancer types. We have recently investigated the impact of Foxc2 gene disruption and FOXC2 overexpression in melanoma on tumor cell adhesion to extracellular matrix (ECM) proteins and lymphatic endothelial cells. We show that melanoma-associated FOXC2 is a critical regulator of tumor cell adhesion to the ECM proteins fibrinogen and fibronectin as well as to lymphatic endothelial cells. These effects on tumor cell adhesion correlate with FOXC2-mediated regulation of the integrins ITGA5 and ITGA9. As changes in cellular adhesion frequently accompany tumor cell transformation and progression, our data suggest that FOXC2 and genes regulated by this transcription factor may play key roles in promoting melanoma invasion and metastasis. Citation Format: Coleman E. Johnson, Corey J. Williams, Kristian M. Hargadon. FOXC2-associated regulation of melanoma cell adhesion to the extracellular matrix and lymphatic endothelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2617.

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Melanoma, a cancer derived from pigment-producing melanocytes of the skin, is a highly aggressive cancer characterized by rapid growth and metastasis. Recent evidence has emerged demonstrating that overexpression of the FOXC2 transcription factor contributes to tumor progression in many cancer types, but the role of FOXC2 in melanoma progression has not previously been studied. Using CRISPR-Cas9 gene editing technology, we have generated and characterized a novel FOXC2 knockout B16-F1 melanoma cell line (B16-F1ΔFOXC2). In comparative in vitro and in vivo studies with wild-type B16-F1 and B16-F1ΔFOXC2 melanomas, we show for the first time that the FOXC2 transcription factor is a critical regulator of melanoma cell growth. The B16-F1ΔFOXC2 melanoma cell line described herein will serve as a useful tool for investigating the function and target genes of FOXC2 in melanoma. Citation Format: Corey J. Williams, Coleman E. Johnson, David Z. Bushhouse, Kristian M. Hargadon. The FOXC2 transcription factor promotes growth of melanoma cells in both in vitro and in vivo settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2610.

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