Melanoma Statistics
Since the mid-1950s the incidence of melanoma has increased faster than any other type of cancer (Erdei & Torres, 2010). The scientists predict that in 2040 the number of new cases will increase to more than 500 000 per year, while the number of melanoma-caused deaths will increase to almost 100 000 per year (Arnold et al., 2022). Melanoma holds the potential for successful treatment if detected and treated in its early stages (stages I and II). On the other hand, the estimated five-year survival rate for patients with regional melanoma that has spread to nearby lymph nodes (stage III) is 64%, while it is only 23% for patients with metastatic melanoma that has spread to other sites in the body (stage IV). Serbia ranks 10th in the world for mortality from melanoma (wcrf.org). Considering these disturbing statistics, the development of an improved antimelanoma strategy is urgently needed and our project aims to contribute to the solution of this problem.
Melanoma can develop through the malignant transformation of melanocytes within a mole.
Melanoma Prevention
Danger of Sun Exposure and Indoor Tanning:
Prolonged exposure to harmful UV radiation from the sun and tanning beds increases the risk of skin damage, premature aging, and most importantly, skin cancer, including the dangerous melanoma.The Importance of Sunscreen Application:
One of the key steps in protecting your skin is the regular and proper application of sunscreen. Sunscreen acts as a shield against harmful UV rays, reducing the risk of sunburn and skin damage.Regular Visits to Dermatologists:
Regular visits to dermatologists play a crucial role in early detection and prevention of melanoma. It is important to schedule routine check-ups with dermatology professionals who can assess your skin's health and address any concerns promptly.Mole Self-Examination using the ABCDE Rule:
This is guidance on how to perform self-examinations of moles using the ABCDE rule:Asymmetry: Check if the mole is asymmetrical, meaning one half is different from the other.
Border: Examine the mole's borders for irregular, jagged, or blurred edges.
Color: Note any changes in color within the mole, including variations or unusual shades.
Diameter: Measure the diameter of the mole; a size larger than a pencil eraser may warrant attention.
Evolution: Monitor the mole over time for any changes in size, shape, color, or symptoms like itching or bleeding.
Background
Metastatic melanomas upregulate aerobic glycolysis to meet their immense energy demands (Avagliano et al., 2020). Moreover, melanoma cells have enlarged, unstable lysosomes that promote their metastasis and drug resistance, but also make tumor cells susceptible to lysosomal membrane permeabilization (LMP), leakage of lysosomal enzymes into the cytoplasm, and cell death (Eriksson et al., 2023). Combining drugs with different mechanisms of action is a central strategy in modern cancer therapy because it improves therapeutic response while attenuates treatment resistance and side effects (Bayat Mokhtari et al., 2017). Although inhibition of glycolysis and induction of LMP have been shown individually to suppress melanoma cell growth (Zhou et al., 2020, Eriksson et al., 2023), the therapeutic effect of this combined approach has not been investigated apart from our previous study (Kosic et al., 2016).
The Project
Our project will explore the anticancer potential of dual targeting of impaired lysosomal stability and overactivated glycolysis in melanoma cells using glucose starvation and clinically approved/investigated drugs. The experiments will be performed using human A375 melanoma cells, both naïve and cells resistant to BRAF inhibitors (previously developed). Melanoma cells will be treated by LMP-inducing drugs (siramesin and mefloquine) in combination with glucose starvation (incubation of cells in a medium without glucose) or inhibitors of glycolytic enzymes (2-deoxy-D-glucose, shikonin, and dichloroacetate). Cell viability and cytotoxicity of treatments will be determined by crystal violet and LDH tests, respectively, and combinations with the strongest/synergistic anti-melanoma effects will be selected for further investigation. The type of cell death (apoptosis, necrosis, autophagic and lysosomal cell death) and its molecular mechanisms (lysosomal membrane permeabilization, energy depletion, oxidative stress, mitochondrial depolarization, concentration, and activation of various molecules) will be determined by flow cytometry, immunoblot, and confocal/electron microscopy, and confirmed by appropriate genetic/pharmacologic inhibition.
MeLyTa PROJECT CONCEPT
MeLyTa Team
Institute for biological research "Sinisa Stankovic"
National Institute of Republic of Serbia, University of Belgrade
Ljubica Harhaji-Trajkovic, PhD
Ljubica Vucicevic, PhD
Nevena Zogovic, PhD
Gordana Tovilovic Kovacevic, PhD
Maja Misirkic Marjanovic, PhD
Kristina Janjetovic, PhD
Ana Despotovic, PhD student
Faculty of Medicine, University of Belgrade
Mihajlo Bosnjak, PhD
Milica Kosic, PhD
Milos Mandic, PhD
Tamara Martinovic, MD PhD
External Partners
Medical Facultyof the Military Medical Academy
University of Defense
Lidija Kandolf Sekulovic, MD PhD
Tatjana Radevic, MD PhD
Milica Rajovic, MD PhD
Institute for Medical Research
National Institute of Republic of Serbia, University of Belgrade
Biljna Ristic, PhD
Milos Mandic received the 2023 Veselin Lucic Award for the best academic achievement by a teacher and collaborator at the University of Belgrade for his research MAP kinase-dependent autophagy controls phorbol myristate acetate-induced macrophage differentiation of HL-60 leukemia cells.
MeLyTa Team received a donation from the nonprofit organization "Climbers Against Cancer" for their research project on September 30, 2023. The check was presented to us at a climbing event in Belgrade by Stasa Gejo, the world junior champion in sport climbing.
Kristina Janjetovic is currently studying how to establish 3D cancer models in Professor Antonio Mazzocca's lab at the Universita degli Studi di Bari Aldo Moro in Bari, Italy.
Dr. Milos Mandic is the recipient of the "Ivan Đaja" award for the best doctoral dissertation in the field of physiology for the academic year 2022/2023, titled: "Interaction of mitogen-activated protein kinases and autophagy in macrophage
differentiation of HL-60 leukemia cells by
phorbol-12-myristate-13-acetate."
