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Reichert, Maximilian; Bakir, Basil; Moreira, Leticia; Pitarresi, Jason R.; Feldmann, Karin; Simon, Lauren; Suzuki, Kensuke; Maddipati, Ravikanth; Rhim, Andrew D.; Schlitter, Anna M.; Kriegsmann, Mark; Weichert, Wilko; Wirth, Matthias; Schuck, Kathleen; Schneider, Günter; Saur, Dieter; Reynolds, Albert B.; Klein-Szanto, Andres J.; Pehlivanoglu, Burcin; Memis, Bahar; Adsay, N. Volkan; Rustgi, Anil K.
Developmental cell, 06/2018, Letnik: 45, Številka: 6Journal Article
The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin (p120ctn)-mediated epithelial identity. Mono-allelic p120ctn loss accelerates KrasG12D-driven pancreatic cancer formation and liver metastasis. Importantly, one p120ctn allele is sufficient for E-CADHERIN-mediated cell adhesion. By contrast, cells with bi-allelic p120ctn loss demonstrate marked lung organotropism; however, rescue with p120ctn isoform 1A restores liver metastasis. In a p120ctn-independent PDAC model, mosaic loss of E-CADHERIN expression reveals selective pressure for E-CADHERIN-positive liver metastasis and E-CADHERIN-negative lung metastasis. Furthermore, human PDAC and liver metastases support the premise that liver metastases exhibit predominantly epithelial characteristics. RNA-seq demonstrates differential induction of pathways associated with metastasis and epithelial-to-mesenchymal transition in p120ctn-deficient versus p120ctn-wild-type cells. Taken together, P120CTN and E-CADHERIN mediated epithelial plasticity is an addition to the conceptual framework underlying metastatic organotropism in pancreatic cancer. •Independent mouse models reveal that liver metastasis requires P120CTN/E-CADHERIN•P120CTN/E-CADHERIN interaction is not required for lung metastasis in these models•p120ctn isoform 1A restoration in p120ctn null cells reinstates liver tropism•Human liver metastases exhibit more epithelial properties relative to primary PDAC The functional basis of metastatic organotropism sheds light on the properties required for successful colonization of distant organs. Reichert et al. demonstrate that epithelial plasticity is a determinant of metastatic organotropism in pancreatic cancer with differing properties required for liver and lung colonization.
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in: SICRIS
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