Researchers have uncovered how the interaction between an essential protein and an endolysosomal ion channel contributes to tumor growth in skin cancer.
LMU researchers have unveiled the mechanisms through which a crucial protein and an endolysosomal ion channel work together to foster tumor development in skin cancer.
Melanoma, which originates from pigment-producing cells called melanocytes, is the most lethal type of skin cancer. One of the primary culprits of melanoma is excessive exposure to ultraviolet (UV) light—whether from the sun or artificial sources—which can lead to mutations that facilitate tumor growth. A research team spearheaded by LMU pharmacologist Professor Christian Grimm from the Walther Straub Institute of Pharmacology and Toxicology, along with Dr. Karin Bartel from the Faculty of Chemistry and Pharmacy, has delved into the molecular processes behind tumor formation. Their research indicates that the collaboration between two proteins—the ion channel TPC2 and the enzyme Rab7a—plays a critical role in enhancing melanoma growth and its spread.
Research has revealed that certain mutations that enhance TPC2 activity are linked to traits such as fair skin, blond hair, and albinism. These characteristics increase a person’s vulnerability to melanoma since their skin is less capable of shielding against harmful UV radiation. In contrast, a lack of TPC2 is connected to a lower risk of melanoma. TPC2 is responsible for facilitating the breakdown of crucial proteins within endolysosomes—cell components involved in transport and degradation—thereby influencing the signaling pathways that govern tumor growth.
Molecular pathways affecting tumor advancement
Similar to TPC2, Rab7a is a significant regulator of the endolysosomal system. Previous proteome analyses have indicated that Rab7a might interact with TPC2. Utilizing advanced techniques like endolysosomal patch-clamp electrophysiology and fluorescence microscopy to measure lysosomal calcium release, the researchers confirmed that Rab7a and TPC2 do interact functionally, which facilitates both the growth and invasiveness of melanoma cells. Furthermore, inhibiting Rab7a pharmacologically resulted in reduced TPC2 activity, consequently slowing melanoma growth.
“Our findings illustrate that Rab7a, by boosting TPC2 activity, is crucial in regulating tumor growth,” states Grimm. “Specific activation of TPC2 by Rab7a lowers the levels of a particular protein that enhances the stability of a transcription factor vital for melanocytes and melanomas, thereby promoting their growth and survival.”
A particularly significant discovery made by the researchers was that the effects of the Rab7a and TPC2 interaction could be observed in living organisms. In mouse models of melanoma lacking either Rab7a or TPC2, researchers noted a significant reduction in tumor size and metastasis. “The relationship between Rab7a and TPC2 could lead to innovative therapeutic approaches targeting the specific signaling pathways that drive melanoma growth and spread,” Grimm concludes.
