Role of E-cadherin in metastatic brain colonization

Brain metastases are associated with a very poor prognosis and frequently occur in patients suffering from breast or colorectal cancer. During the process of metastatic colonization, successfully disseminated cancer cells settle in the brain and progress into macro-metastases. In this context, we recently summarized significant morphological differences at the macro-metastases/organ parenchyma interface (MMPI) with a strong influence on prognosis in several studies. While displacing metastases usually displayed a more favorable prognosis, infiltrative metastases had an unfavorable disease progression. Since diffuse and epithelial infiltrative cells differed in their pathophysiology, the aim of this study was to investigate the potentially responsible mechanisms underlying this difference. In our lab, we previously established a variety of brain metastasis mouse models that allow the detailed characterization of the MMPI on a morphological and molecular basis. Interestingly, diffuse and epithelial infiltrative models showed differences in their innate expression levels of the cell adhesion receptor E-cadherin across species and entities. However, we hypothesized that E-cadherin is not only a marker for the type of infiltration, but also plays a critical functional role. Thus, we performed specific opposing genetic modifications of E-cadherin in the corresponding cell lines of our brain metastasis mouse models representing the different infiltrative MMPI patterns to investigate the impact on the infiltration pattern and the metastatic microenvironment. Although both genetic approaches provoked profound phenotypic changes, they had no influence on the original characteristic of the cell. Nevertheless, the gain of E-cadherin decreased migratory and invasive capacity in vitro, while the artificial loss made cells more invasive across entities. This was reflected in the animal model with less aggressive metastases and prolonged survival after the overexpression of E-cadherin and increased aggressiveness and shortened survival in the knockdown cohorts. The switch of the infiltration pattern due to the E-cadherin modification in the metastatic outgrowth models, from diffuse to epithelial-like infiltrative after the gain of E-cadherin and the other way around after its loss, further resulted in an altered immune reaction of the metastatic microenvironment. In general, diffuse infiltrative patterns were associated with an increased immune response at the MMPI. Furthermore, we could establish a gene expression signature that clearly differentiated diffuse and epithelial infiltrative mouse models based on their metastatic cell character and even had a prognostic impact in murine and human metastases. In conclusion, these data emphasize the essential role of the MMPI during metastatic colonization of the brain and might contribute to MMPI pattern-based therapeutic decisions for cancer patients in the future. The identified gene targets could represent a prognostic tool to classify the outcome of patients with metastases based on the analysis of their tumor gene expression signature