Expression of POU2F3 Transcription Factor Control Inflammation, Immunological Recruitment and Metastasis of Pancreatic Cancer in Mice

SIMPLE SUMMARY: The presence and the role of TUFT cells in pancreatic ductal adenocarcinoma (PDAC) is discussed. Therefore, we decided to inactivate the POU2F3 gene, which is essential for TUFT cells development, in an aggressive PDAC mice model known as PDX1-Cre;LSL-Kras(G12D);Ink4a(fl/fl). Morphological and molecular analysis of POU2F3-deleted PDAC show not significant changes in tumors growth and survival of animals although it promotes EMT. Remarkably, we observed that in POU2F3-deleted animals the lack of TUFT cells prevents metastasis formation and strongly modifies the immunological and inflammatory landscape. ABSTRACT: TUFT cells have been described as strong modulators of inflammatory cells in several tissues including pancreas. TUFT cells, also known as DCLK1(+) cells, are dependent of the transcriptional factor POU2F3. Several works report DCLK1(+) cells in early stages of PDAC development suggesting an important role of TUFT cells in PDAC development. Therefore, we developed a mice model (PDX1-Cre;Kras(G12D);Ink4a(fl/fl)), known as PKI model, deficient or not of POU2F3. In this animal model, deficiency of POU2F3 results in the absence of TUFT cells in PDAC as expected. Although, tumor development and growth are not significantly influenced, the development of liver metastasis was almost completely inhibited in POU2F3-deficient mice. Surprisingly, the absence of metastasis was associated with a higher expression of epithelial-to-mesenchymal transition markers, but to a lower inflammatory microenvironment suggesting that inflammation influences metastasis production more than epithelial-to-mesenchymal transition in this animal model. We can conclude that POU2F3 could be a new therapeutic target for control PDAC progression.