Sox4-dependent acinar cell plasticity in pancreatic regeneration and cancer initiation.

Introduction:
The pancreas is composed principally of secretory acinar cells. Upon acute inflammation of the pancreas, acinar cells reprogram and activate a molecular program enabling pancreas regeneration. However, somatic mutations in the Kras proto-oncogene prevents pancreas regeneration and induce neoplastic transformation of acinar cells, which develop into precursor lesions of pancreatic cancer (PanINs). We aim to unravel the function of a transcription factors which is i) conserved in mouse and human and ii) de novo expressed upon acinar regeneration and transformation.

Material and Method:
We used the Ptf1aCreER mice to conditionally drive the expression of YFP, KrasG12D (K) and delete Sox4 (S) in adult pancreatic acinar cells analyzing 4 mouse strains, Cacinar, CSacinar, KCacinar and KCSacinar. Tissue injury is induced by caerulein. Analysis for reprogramming and transformation is, respectively, 2- and 21-days post-injury. Human primary exocrine explants were cultured in suspension and mimic human acute pancreatitis. Human pancreatic cancer samples were analysed. We made use of RNA in situ hybridisation, qRT-PCR and immunohistochemistry to unravel and validate our findings.

Results and discussion:
Here, we report a role of Sox4 in cellular differentiation, proliferation, and survival of pancreatic acinar cells in a model of regeneration and cancer initiation after induction of tissue injury in the adult mouse pancreas. De novo expression of Sox4 is conserved in injured human exocrine acinar cells and in clinical samples of chronic pancreatitis and PDAC. Loss of Sox4 in the process of regeneration decreases acinar proliferation and cell death and increases the expression of transcription factors associated with PanINs. The exacerbated wound-healing response, exemplified by activated Stat3 signaling in metaplastic acinar cells, is associated with activation of fibroblasts to a myofibroblast phenotype with extensive deposition of ECM-associated proteins. In the context of KrasG12D-mediated transformation of acinar cells to PanINs, we report a loss of differentiation to Muc5Ac+ mucin-producing cells and Dclk1+ tuft-like cells with appearance of Cldn4+ flattened epithelium. An equal loss of proliferative capacity and cell death is observed with increase of senescent markers. Furthermore, we observe a remodeling of the immune landscape and activation of the innate and adaptive immune system.

Conclusion:
We propose a tumor-suppressive role of Sox4 in acinar regeneration and cancer initiation, alleviating the wound-healing response and promoting cellular differentiation in cancer initiation.