Endolysosomal cation channels as novel targets for cancer therapy

• Applicants: Dr. Karin Bartel; Professor Dr. Christian Michael Grimm
• Subject Area: Pharmacology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388209774

Endolysosomal two-pore channels (TPCs) and mucolipins (MCOLNs, TRPMLs) are controlling intracellular trafficking and transport, and affect cell proliferation, migration, invasion, and autophagy. Although our understanding of the roles, in particular of TRPML1 and TPC2 in cancer biology has deepened, many open questions remain. In this proposal we would like to focus on further elucidating the roles of TRPML1 and TPC2 in skin cancer (melanoma) and liver cancer (hepatocellular carcinoma, HCC) and we want to investigate the crosstalk between cancer cells and immune cells in which TPCs and TRPML channels are particularly highly expressed, e.g. in macrophages. While many cancer incidences are falling, the incidence rate of malignant melanoma is rising at a rate of 3-7% in most European countries versus 2.6% in the US, and is expected to rise further. There are about 100,000 new cases per year in Europe and the US, each, with approximately 22,000 deaths per year in Europe and 7,000 in the US. When discovered early, melanoma can be surgically dissected and patients have a high chance of being cured. However, when metastases have already formed, the prognosis is generally very poor, going along with a strongly decreased life expectancy, highlighting the importance of early diagnosis but also the need for new effective melanoma treatments. On the other hand, HCC is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the US, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. HCC is an inflammation-associated cancer and macrophages play a crucial role in chronic liver inflammation, and the tumor microenvironment plays a key role in the progression of HCC. Tumor-associated macrophages are a well-known component of the tumor microenvironment and abundantly infiltrate the HCC microenvironment. A deep understanding of macrophages in HCC will be critical for developing effective HCC therapy and targeting macrophages might provide a novel therapeutic approach for HCC patients. In this proposal, we will establish co-cultures of cancer cells and immune cells (WT and TRPML1/TPC2 KOs) to investigate the effects of a pharmacological blockage or knockout of TRPML1, TPC2, or both in immune cells (macrophages) as well as cancer cells, and we will investigate how macrophages, both pro- and anti-inflammatory ones affect cancer cell hallmarks. In addition, we will assess differences between single and double knockout of TRPML1 and TPC2 on cancer hallmarks in melanoma and HCC cells. Finally, we would like to better understand the roles of TRPML1 and TPC2 in cancer development by reprograming melanocytes or hepatocytes (WT and TRPML1/TPC2 KOs) to develop into melanoma cells and HCC, or by using hiPSC (WT and TRPML1/TPC2 KOs) to develop into tumorigenic cells in-vitro.

• DFG Programme: Research Grants