1. The role of ROR1 pseudokinase in cancer development
Identifying the regulatory mechanisms associated with pseudokinases-mediated cancer development in preclinical models is crucially important and the first-line approach when working with uncharacterized signaling molecules. We have undertaken a comprehensive approach to study the regulation of ROR1 signaling in mantle cell lymphoma (MCL) and B-cell acute lymphoblastic leukemia (B-ALL), both diseases with high expression of ROR1. By employing an array of several molecular biology techniques (lentivirus-mediated knockdown, siRNA, high throughput drug sensitivity and resistance testing (DSRT), mAb treatments in cell lines and ex vivo patient samples), we showed that ROR1 expression is directly linked to NF-kB or STAT3 activation and identified combinatorial drug-treatments that are more efficient in augmenting ROR1 targeted therapies in these diseases (Karvonen et al, Blood Adv, 2017; Karvonen et al, Oncogene 2019).
Similar strategies are now applied by us to investigate the role of Wnt5a-ROR1 signaling in stemness and drug resistance development in ovarian cancer and glioblastoma.
2. Wnt ligand binding and signal initiation at the receptor level
We will continue our research line and collaborations to unravel the molecular mechanisms of Wnt-ligand binding and signal initiation at the receptor level. Specific questions that we plan to address are the role of the C-terminus domains of ROR1/ROR2 and the mechanism of signal initiation, whether is conformation-mediated scaffolding of intracellular adapters and/or other uncharacterized mechanisms.