The major cause of death in cancer patients is a combination of metastatic dissemination combined with therapy resistance. Over recent years, intratumour phenotypic heterogeneity arising from the bi-directional interplay between plastic cancer cells and the microenvironment has been identified as key to disease progression. Most notably metastatic outgrowth and resistance to targeted therapies are frequently associated with activity of mTORC1, a key metabolic hub that promotes protein synthesis and proliferation in the presence of nutrients.
However, while the regulation of mTORC1 by amino acids and glucose availability is well characterized, whether other mechanisms are important in controlling mTORC1 and its downstream signalling is less well understood. The Parrington group has shown that mTORC1 activity is decreased following the knockout (KO) in melanoma cells of TPC1, a cation channel localised to early and recycling endosomes. Consequently, TPC1 KO melanoma cells exhibit reduced proliferation and invasiveness, as well as increased pigmentation associated with nuclear localisation of the MITF-related transcription factor TFEB. The results demonstrate that the knockout of TPC1 has induced significant tumour-suppressive effects in melanoma, during which the altered activity of mTORC1 and TFEB play the key roles.
The study is published in Heliyon and available online on ttps://authors.elsevier.com/sd/article/S2405-8440(24)15783-0