STARD3: A new potential therapeutic target in colorectal cancer

Colorectal cancer (CRC) is the third leading cause of cancer death in Europe, with a prevalence of more than a million cases every year. Primary or acquired resistances to therapies are the major limits to be addressed. The overall five years survival rate is less than 10% for stage IV and only a fraction of the tumours respond to available therapies (Van Der Jeught et al., 2018). There is a crucial need for new therapeutic biomarkers to avoid CRC-related deaths (Vacante et al., 2018).        In this scenario, cholesterol metabolism has received increasing attention due to its role in cancer development. Cancer cells show higher levels of intracellular cholesterol compared to normal cells. Tumour cells require high amounts of lipids, nucleic acids and proteins for their survival. Cancer cells increase the de novo lipid biosynthesis including cholesterol synthesis (Currie et al., 2013). Cellular cholesterol metabolism, including intracellular distribution, is highly coordinated and controlled by a complex protein network. Between them, StAR-related lipid transfer domain-3 (STARD3) regulates the cholesterol accumulation in endosomes and mediates its inter-organelle distribution.There are different studies suggesting STARD3 is associated with several cancer types: STARD3 is highly expressed in 25% cases of breast carcinoma and high STARD3 levels have been correlated with poor overall survival, disease metastasis-free survival and relapse-free survival (Vassilev, B et al., 2015); and it is associated with shorter patient survival in colon, liver and renal cancer patients (Protein Atlas).This research project aims to demonstrate STARD3 is a valid therapeutic target for colorectal cancer patients. we identified STARD3 as a key player, which regulates different aspects of hallmark of cancer. Our hypothesis is that STARD3 is a valid therapeutic target for mCRC patients. This hypothesis is based on the following thesis results here summarized: a) STARD3 is overexpressed in CRC tumors tissue compared to normal tissue and correlate with patient's survival. b) Despite cancer cells contain complex genetic alterations, growth and survival can be affected by STARD3 single inactivation. c) Inhibition of STARD3 (both with short hairpins and drugs) induces apoptosis in colorectal cancer cell lines and in a subset of patient derived organoids and inhibit tumor formation in vivo. d) STARD3 overexpression transforms normal mouse colon organoids, inducing tumour formation in vivo (oncogene).