Scientists identify key mechanism in development of skin cancer

Melanoma arising from pigment-producing cells known as melanocytes is the deadliest form of skin cancer. A major cause of melanoma is excessive exposure to ultraviolet light, from sunlight or other sources, which can trigger mutations that promote tumor formation. A team led by LMU pharmacologist Professor Christian Grimm (Walther Straub Institute of Pharmacology and Toxicology) and Dr. Karin Bartel (Faculty of Chemistry and Pharmacy) has now investigated the molecular mechanisms of tumorigenesis. As the researchers demonstrate, the interplay of two proteins – the ion channel TPC2 and the enzyme Rab7a – plays a decisive role, as they promote the growth and metastasis of melanoma.

Studies have shown that certain activity-boosting mutations in the ion channel TPC2 are associated with fair skin, blond hair, and albinism. These traits make people particularly susceptible to melanoma, as their skin offers less protection against harmful ultraviolet radiation. Conversely, loss of TPC2 is associated with decreased melanoma risk. The ion channel controls the breakdown of important proteins in endolysosomes – cell organelles that are involved in transport and degradation processes – and thus influences signaling pathways that regulate tumor growth.

Molecular pathways influencing tumor progression

Like TPC2, the protein Rab7a is an important regulator for the endolysosomal system. Earlier proteome analyses had shown, moreover, that Rab7a is a potential interaction partner of TPC2. Using modern methods such as endolysosomal patch-clamp electrophysiology and the measurement of lysosomal calcium release via fluorescence microscopy, the researchers established that there was indeed an interaction between Rab7a and TPC2 at the functional level, which promoted the growth and invasiveness of melanoma cells. Conversely, the pharmacological inhibition of Rab7a decreased TPC2 activity and thus melanoma growth.

“Our results show that Rab7a, by amplifying TPC2 activity, plays a key role in the regulation of tumor growth,” says Grimm. “Specifically, the activation of TPC2 by Rab7a reduces the levels of a certain protein. This protein boosts the stability of a transcription factor that is a key regulator in melanocytes and melanomas and promotes their proliferation and survival.”

A particularly notable finding, according to the researchers, was that effects of the interaction of Rab7a and TPC2 could be demonstrated in vivo. In mouse models with melanoma cells without Rab7a or TPC2, they found that tumor size and metastasis were much reduced. “The interaction between Rab7a and TPC2 could pave the way for new therapeutic strategies which target the specific signaling pathways that promote melanoma growth and metastasis” concludes Grimm.

C. Abrahamian et al.: Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis. Nature Communications 2024