Abstract 2551: Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance

Abstract

Abstract Melanoma is a disease of ageing with elderly patients showing poorer prognosis than younger patients. The role of the ageing microenvironment in melanoma progression is now recognized where aged stromal cells undergo cellular and molecular changes that are tumour permissive. However, sex-based differences in melanoma incidence and outcome have also been observed even when adjusted for several prognostic factors including age, with men having poorer outcomes compared to women. While the mechanisms underlying this disparity are not well understood but attributed to sex-specific behaviors as well as to the biologically intrinsic differences. In addition, most preclinical studies have ignored the contribution of the host sex and age to therapy response, with majority of the studies typically performed in 6-8 week old male mice. Dermal fibroblasts (dFs) are established to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in dFs can alter the course of melanoma tumor growth, visceral metastasis, dormancy and variable responses to targeted therapy. We find that age-matched female dFs undergo early replicative senescence accompanied by reduced proliferation and morphology change. Despite being senescent, age-matched female dFs showed reduced SASP characteristics. This was assessed by testing dFs derived conditioned media on melanoma cells in spheroid invasion and resistance to BRAF/MEK inhibition which showed elevated expression of invasive drivers and oxidative stress from aged male dFs derived conditioned media. This was also apparent in vivo in syngeneic immunocompetent C57Bl/6 mice that showed reduced tumor growth and increased invasion specific to the aged male host. Our data provides an integrated view of how age and sex attributes of dFs within the microenvironment contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare. Citation Format: Yash Chhabra, Mitchell Fane, Laura Huser, Daniel Zabransky, Megan Brezka, Gloria Marino, Alexis Carey, Ashani Weeraratna. Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2551.