Abstract 5410: Unveiling PAI-1 as a new player in chemoresistant melanoma in aged human skin reconstructed in vitro

Abstract

Abstract The impact of advanced glycation end products (AGEs) accumulation is associated with the development and exacerbation of many degenerative processes and disorders, including aging and cancer. AGEs accumulation in the skin leads to stiffness and loss of elasticity by building up in the connective tissue during aging process. This process has implications of the extracellular matrix, affecting the adhesion, migration, and invasiveness potential of melanoma cells. Furthermore, tumor invasiveness is correlated with mechanical stiffness, contributing to the high metastatic capacity of melanoma. To address this research gap, our study aimed to evaluate the invasive potential of chemoresistant melanoma using an in vitro model of reconstructed aged human skin modified by glycation. Glycated skin exhibited distinct features indicative of aging, including positive pentosidine fluorescence and elevated CML labeling and expression, well-established biomarkers of aging. Furthermore, glycated skin with resistant melanoma demonstrated reduced expression of differentiated keratinocytes (CK-10) and increased expression of undifferentiated keratinocytes (CK-14). Overall, in glycated skin with resistant melanoma, decreased proliferation and increased tumor invasion were observed, associated with changes in the expression of key markers, such as reduced MITF and SOX-10 and increased AXL. Downregulation of MITF in skin with resistant melanoma resulted in decreased Melan-A expression, implying altered pigmentation of melanoma cells. Additionally, resistant melanoma in glycated skin showed enhanced inflammation, as indicated by higher levels of IL-8 and IL-1α. Gene screening showed upregulation of the PAI-1, ABL-1, COL1A1, SPARC genes. Among these genes, PAI-1 (Plasminogen activator inhibitor-1) was upregulated in resistant melanoma compared to naïve melanoma both in glycated skin. PAI-1 may play a critical role in the development of aging-associated pathological changes. In addition, PAI-1 is recognized as a marker of senescence and a key member of a group of proteins collectively known as the senescence-messaging secretome. It also performs protumorigenic functions, such as promoting vasculature, increasing growth, motility and protecting tumor cell apoptosis. Overall, this work demonstrated that skin aged by glycation when associated with i-Braf resistant melanoma exhibited a more invasive and less proliferative profile (low MITF and SOX10, elevated AXL), more inflammatory (elevated IL-8 and IL-1α) and with a greater number of immature keratinocytes (elevated ck-14). PAI-1 overexpression may be a promising target to expand studies caused by oncogenes in the model of aged skin by glycation with resistant melanoma. Citation Format: Renaira Oliveira da Silva, Larissa A. Carvalho, Denisse E. Camarena, Julia R. Silva, Isabella H. Noma, Manoel O. Moraes, Paula C. Pennacchi, Silvya S. Maria Engler. Unveiling PAI-1 as a new player in chemoresistant melanoma in aged human skin reconstructed in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5410.