Marie R. Webster

Tumor heterogeneity and plasticity enable adaptation to metastatic microenvironments and resistance to therapies. Recent progress in single-cell analyses has permitted detailed characterization of the complexity and diversity of the different tumor components in multiple tumor types. Cancer-associated fibroblasts (CAF) are a central component of the tumor microenvironment and play critical roles in cancer progression and therapeutic response. The identification of different CAF subtypes and elucidation of their functional plasticity are crucial for identifying novel therapeutic approaches to target protumorigenic CAFs and harness tumor-suppressive CAFs to enhance the efficacy of cancer treatments. In this review, we discuss how intrinsic and extrinsic factors and the extensive cross-talk between cancer cells and the tumor microenvironment promote CAF heterogeneity and their contributions to cancer progression and therapeutic resistance. Understanding the roles of CAF plasticity and their intercellular interactions may drive the development of effective treatment strategies to improve patient prognosis.

The Society for Melanoma Research (SMR) was created 20 years ago and has unequivocally contributed to the vast progress of the field, particularly for the treatment of melanoma patients with metastatic disease by facilitating synergistic collaborations between clinicians, researchers at the bench, and industry. In commemoration of the 20th anniversary of the first SMR International Congress (held in 2003 in Philadelphia), we look to the future by highlighting the perspectives of the next generation of rising stars, medical, and graduate students across six continents.

Upon the 20th Anniversary of the Society for Melanoma Research, we highlight the perspectives of patients aiming to help improve future experiences, outcomes, and their quality of life over the next 20 years. Five melanoma patients generously shared their inspiring and enlightening stories of diagnosis, treatment, and outcomes. Many patients had excellent medical teams that synergistically worked together to provide an accurate diagnosis, effective treatment options, and supportive care. However, it is clear that health inequities persist in communities where people of color are predominant, affecting early detection, patient experience, and outcomes. These stories shed light on the unique challenges faced by patients and how the lack of melanoma awareness and adequate resources, especially in communities of color or low socioeconomic status, can contribute to disparate outcomes in melanoma care. We expect that these stories will raise awareness about the progress in melanoma treatment but also the existent disparities in melanoma diagnosis and treatment and the importance of early detection and prevention.

To commemorate the 20th Anniversary of the Society of Melanoma Research and the first International Melanoma Research Congress held in June of 2003, we have described in brief, how the Society for Melanoma Research (SMR) began, the purpose, goals, and governance of the SMR, and how the society has evolved to support new melanoma researchers. In celebration of the immense progress in treating melanoma patients over the last 20 years and the impact of the SMR on these advances, we have highlighted memories and insight from early SMR members and founders.

Aged BODIPY-C12 fibroblasts with GFP-tagged melanoma cells

Aged BODIPY-C12 fibroblasts with GFP-tagged melanoma cells

Supplementary Figures and Legends.

Supplementary Figures and Legends.

Older patients with melanoma (>50 years old) have poorer prognoses and response rates to targeted therapy compared with young patients (<50 years old), which can be driven, in part, by the aged microenvironment. Here, we show that aged dermal fibroblasts increase the secretion of neutral lipids, especially ceramides. When melanoma cells are exposed to the aged fibroblast lipid secretome, or cocultured with aged fibroblasts, they increase the uptake of lipids via the fatty acid transporter FATP2, which is upregulated in melanoma cells in the aged microenvironment and known to play roles in lipid synthesis and accumulation. We show that blocking FATP2 in melanoma cells in an aged microenvironment inhibits their accumulation of lipids and disrupts their mitochondrial metabolism. Inhibiting FATP2 overcomes age-related resistance to BRAF/MEK inhibition in animal models, ablates tumor relapse, and significantly extends survival time in older animals.Significance:These data show that melanoma cells take up lipids from aged fibroblasts, via FATP2, and use them to resist targeted therapy. The response to targeted therapy is altered in aged individuals because of the influences of the aged microenvironment, and these data suggest FATP2 as a target to overcome resistance.See related commentary by Montal and White, p. 1255..This article is highlighted in the In This Issue feature, p. 1241