Epithelial barrier function and its underlying mechanical regulation affects the biology of Macro-Metastasis Parenchyma Interface (MMPI).

Already years ago, the histopathological growth pattern (HGP) of liver metastases at the macro-metastases parenchyma interface (MMPIliver) was included in pathological guidelines. Brain metastases also differ in their HGPs at the MMPIbrain. However, there is no existing biological concept for these differences. Pathophysiological, the MMPI is an interface between an emerging metastatic tissue and the host organ, which both protect themselves from each other. Thus, it would be not surprising that carcinomas reactivate their original function, the epithelial barrier at this interface. However, differences in epithelial barrier were never been taking into account for different HGPs at the MMPI. Here, we systematically compared models with epithelial infiltration (Epi-models) with diffuse infiltrating models (Diff-models) at the MMPIbrain. Using this stratification, we revealed fundamental differences in mechano-transduction via YAP, Ca2+ distribution and the epithelial barrier function. Moreover, these features have effects on immune cell infiltration and druggable immune checkpoints. Finally, we clustered human brain and liver metastases by using an Epi- and a Diff-gene signature into four clusters: the Epi-, Diff-, Mixed- and Unclassified-cluster. These also revealed enormous differences in pathways, responsible for epithelial barrier formation, extracellular matrix and immune response. Moreover, it also revealed YAP as an important transcriptional co-activator in this context. Taken together, we report about fundamental differences in barrier function and mechano-regulation at the MMPI, which could have implications for therapy decisions of metastasized patients in future. We collected 28 brain metastatic samples from patients (one sample per patient) previously diagnosed with colon cancer (n=16) and rectal cancer (n=12), and characterized them by RNA-Seq.