Blocking Lipocalin-2 (Lcn-2) using Nanobodies as novel cancer therapy

Tumors are organ-like tissues consisting of cancer cells, structural and immune cells, blood vessels and connective tissue, which collectively form the tumor microenvironment. Some of these immune cells, i.e. tumor-associated macrophages (TAMs), act in a tumorpromoting manner, since their normal function is hijacked by the tumor.

Cancer cells use TAMs to acquire essential nutrients, including iron, thereby providing optimal conditions for their survival and metastasis. Hereby, Lipocalin-2 (Lcn-2) may play a crucial role, as it delivers iron to rapidly proliferating cells, such as cancer cells, and can polarize TAMs into a pro-tumoral behaviour. Hence, Lcn-2 significantly promotes the initiation, progression, and metastasis of various cancer types and its aberrant expression correlates with the chemo- and radioresistant phenotype of tumors..

In this proposal, we will evaluate the potential of newly generated anti-Lcn-2 Nanobodies to block Lcn-2 functions and to mediate a more favorable tumor outcome, either as monotherapy or in combination with existing therapies. To this end, we will use the metastatic E0771.LMB mouse model of triple-negative breast cancer (TNBC), that exhibits high Lcn-2 expression levels. TNBC remains associated with high aggressiveness and elevated rates of metastasis and exhibits a poorer clinical prognosis and a higher mortality rate than other types of breast cancer. Hence, Lcn-2 blockade may be a novel therapeutic avenue for this type of cancer.