Decoding the role of cadherin 11 in early cancer dissemination, dormancy and metastatic reactivation

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The spread of cancer throughout the body, termed metastasis, is responsible for 90% of cancer-related deaths. Despite the complexity of cancer dissemination, there is increasing evidence for cancer cells leaving the primary site very early in cancer evolution (e.g. in-situ state). These early disseminated tumor cells (eDTCs) lodge in secondary organs, where they often remain silent for years to decades, a process called dormancy. However, DTCs can re-activate proliferative programs and cause late metastatic relapse. The aim of this project is to decode the mechanism of early dissemination and breast cancer dormancy, with a special emphasis on the functional influence of the adhesion protein cadherin 11 (CDH11). Our preliminary data suggests a pro-invasive/disseminating and anti-proliferative role of CDH11 in early HER2+ breast cancer. Hence, we suggest a role of CDH11 in dissemination of pre-malignant early lesions, as well as eDTC dormancy in the bone marrow (BM), liver and lung. In depth studies of the expression dynamics in vitro and in vivo, exploiting 3D organoid culture, inducible knockout (KO) systems, single cell sequencing, as well as a CDH11-reporter mouse and intravital imaging will allow to decipher distinct functional roles of CDH11 during dormancy and metastatic reactivation of breast cancer. We also aim to determine niche components of CDH11 positive or negative DTCs, which may mediate cancer cell dormancy or metastatic reactivation. On the basis of detailed understanding of the regulation and signaling of CDH11, we aim to develop strategies to specifically target dormancy and late recurrence of breast cancer.