Proteomic signatures of Mitochondrial and immune responses as predictors of melanoma evolution

Melanoma, characterized by its high metastatic potential and recurrence, presents a complex interplay of genetic, metabolic, and immune mechanisms. Recent advances have elucidated the key roles of mitochondrial dysfunction and immune evasion in the progression and recurrence of melanoma1,2. These insights pave the way for novel therapeutic targets and prognostic biomarkers, enhancing our capacity for personalized treatment strategies.

Recently, we have shown that mitochondrial dysregulation is a hallmark of aggressive melanoma phenotypes, particularly influencing tumor cell metabolism and resistance to apoptosis3. The mitochondrial translation machinery, crucial for biosynthetic processes, exhibits notable alterations in melanoma, leading to metabolic reprogramming. Enhanced mitochondrial biogenesis and function have been linked with increased tumor aggressiveness and poor prognosis due to their role in sustaining proliferative and invasive tumor characteristics4. Concurrent with mitochondrial alterations, melanoma cells deploy sophisticated strategies to evade immune surveillance5. Mutation and downregulation of major histocompatibility complex (MHC) molecules and upregulation of immune checkpoint ligands, such as PD-L1, allow melanoma cells to remain undetected by the immune system. Furthermore, the tumor microenvironment is modulated to suppress effective immune responses, facilitating tumor growth and metastasis.

We have generated and leveraged data from extensive proteomic and genomic analyses on clinical samples. Our research underscores the significant interaction between mitochondrial dysregulation and immune responses. For instance, proteomic profiling has identified distinct mitochondrial and immune signatures that differentiate recurrent melanomas from non-recurrent ones. These signatures not only enhance our understanding of melanoma biology but also highlight potential biomarkers for early detection of recurrence. Targeting mitochondrial pathways offers a promising therapeutic avenue. We have shown that agents that disrupt mitochondrial functions, such as oxidative phosphorylation and mitochondrial translation inhibitors, have shown efficacy in cellular models by inducing metabolic crisis in melanoma cells.

The integration of mitochondrial and immune signatures provides a comprehensive understanding of melanoma's aggressive nature and recurrence, supported by ongoing clinical trials focusing on these pathways. This presentation underscores the importance of multi-omics approaches in unraveling the complex biology of melanoma, setting the stage for future breakthroughs in melanoma management.

References

Szadai, L. et al. Clin Transl Med 13, e1495 (2023).Gil, J. et al. Cancers (Basel) 13, (2021).Gil, J. et al. bioRxiv 2022.10.24.513481 (2022)Pinto, N. et al. Submitted (2024).Gil, J. et al. bioRxiv 2021.04.10.439245 (2021)