IRAK2 depletion renders breast cancer stem cells non-tumorigenic via differentiation

• Applicant: Privatdozent Dr. Jochen Maurer
• Subject Area: Gynaecology and Obstetrics ; Hematology, Oncology ; Cell Biology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407869199

In recent years, developmental pathways and traits have gained interest in the search of novel agents for cancer therapy. In addition, our established models for investigative/experimental designs are based on developmental concepts. In particular, cancer cells with the characteristics of stem cells have been of interest in hematopoietic malignancies as well as solid tumors, influencing the way we define tumorigenesis.These so called cancer stem cells (CSCs) are thought to be the motor of tumor growth and expansion. They are chemoresistant, sometimes quiescent and the origin of metastasis. Several surface markers are discussed as specific for a given cancer tissue type and screening efforts are underway to target these cells in particular. Nevertheless most efforts lack a clear foundation, because CSCs are hard to isolate, propagate or purify. Additionally, classical targeting strategies aim to kill these cells with the known side effects of current medical therapies.We identified a novel method to isolate and cultivate CSCs from human patient tumors of triple negative breast cancer (TNBC). The CSCs can be expanded for analytical purpose and to identify modes of action of target genes and novel therapies. The cells are highly tumorigenic with as few as 1000 cells recapitulating the patient’s tumor of origin in immunocompromised animals to a likeness making it hard for a pathologist to tell patient and xenograft apart. In parallel, we identified kinases responsible for cancer stem cell maintenance in triple negative breast cancer. Among others, we identified kinases ALPK1 and ERN1 as gatekeepers for cancer stem cell self-renewal and differentiation, showing for the first time that knockdown of these kinases elicits a differentiation response in bipotent tumor initiating cells of TNBC. This luminal-like differentiation rendered the cells incapable of tumor formation. One additional kinase identified in said screen was Interleukin-1 receptor-associated kinase-like 2 (IRAK2). Like ERN1 and ALPK1, IRAK2 was capable of driving cells towards a luminal fate. Interestingly, IRAK2 is also one of the most highly enriched genes in CSC cultures from primary TNBC patients varying in intensity from patient to patient. In this proposal we want to investigate the role of IRAK2 in maintenance of CSCs from TNBC, elucidate its mode of action and its clinical significance and finally identify novel therapeutics targeting IRAK2. Using our unique human CSC cultures from TNBC patients, we will generate direct applicability to the clinic and fulfill the medical need. The idea to manipulate stemness features of a given cancer rather than aiming for selective cell death opens up alternative treatment possibilities which might benefit the patient in the years to come.

• DFG Programme: Research Grants