Triple Negative Breast Cancer (TNBC) is the most aggressive form of breast cancer. High mortality rate due to cancer attributes to spreading tendency of cancer cells to other organs of the body due to lack of specialised treatment for specific cancer.
KIPA for searching TNBC vulnerabilities
“‘In this study, published in PNAS Nexus, we went and searched for enzymes called kinases, which are which are frequently ‘turned on,’ or overexpressed, in cancers,’ said first author, Dr. Junkai Wang, who was a member of the Foulds lab at the time he worked on this research.”
“Wang explained that the challenge was to isolate the kinase out of hundreds of kinases across the TNBC cells that could capitalise on the mutation in the kinase to take the upper hand on this cancer.”
In the case of kinase identification among hundreds of potential candidates, the researchers had previously developed a laboratory method, called the kinase inhibitor pull down assay (KIPA) which significantly speeds up kinase identification.
A new role for DAPK3
In further studies, it was discovered that knocking out the DAPK3 gene, therefore also eliminating the DAPK3 protein, also prevented migration and invasion of TNBC cells in lab experiments, but did not affect cancer cell growth. In immunocompromised mice, when TNBC cells with DAPK3 knocked out were grown as tumours, there was no significant effect on tumour metastases. A definite result will require additional modelling of metastases.
They also learned how DAPK3 promotes its movement behaviours.
“We found that DAPK3 reduces the levels of desmoplakin (DSP), a protein involved in regulating cell adhesion, which is also important for a cell’s ability to migrate,” Wang said. “We also found that a protein called LUZP1 grips DAPK3 and saves it from being destroyed by the cell.”
Foulds said: “Overall, we have learnt more about what kinases influence the spread of TNBC cells.” “We used to believe that a cancer driver, which we interpret as an effect that regulates cell proliferation, alters the movement of the cells.” However, we saw that DAPK3 did not regulate growth in TNBC but instead invasion and migration.
To learn more about how the DAPK3/LUZP1 complex promotes TNBC migration and to determine whether it is a potential therapeutic target, we move forward with additional studies.
Reference: Ana María Rodríguez. DAPK3 emerges as a new regulator of migration of triple-negative breast cancer cells.
