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

Gene alterations play a prominent role in driving cancer initiation and progression. Yet, mutations on oncogenes (those genes that promote tumorigenesis) only transform cells under certain cellular contexts. The mechanisms controlling neoplastic transformation (oncogenic competence) are poorly understood in pancreatic ductal adenocarcinoma (PDAC). Our laboratory investigates the interplay of mutations on the Kirsten Rat Sarcoma oncogene (Kras), developmental transcriptional programs, and the tissue microenvironment PDAC initiation. Our data demonstrate that Sox4 is necessary for the specification of cellular states in preinvasive cancer lesions and regulates the characteristics and cellular compositions of the tumor microenvironment in an autochthonous genetic model of PDAC. The pancreas has a remarkable ability to regenerate and recover from acute pancreatitis. In this process, acinar cells repress the expression of genes associated with acinar function and transiently activate a gene program that resembles pancreas progenitors of development. This mechanism, defined as cellular plasticity, alleviates tissue damage, stimulates acinar proliferation, and is necessary for pancreas regeneration. However, it makes the acinar cells competent to malignant transformation mediated by Kras. To investigate SOX4 function in pancreas regeneration and cancer, we used the KCacinar mouse model (Ptf1a-CreER; Kras G12DLSL). After injury, we observed a transient four-fold increase in the expression of SOX4, which correlates with the morphological and molecular evidence of cellular plasticity. KCacinar mice rapidly develop mucinous pancreatic intraepithelial neoplasias (PanINs) after caerulein-induced pancreatitis. Histological analysis KCAcinar Sox4-depleted pancreas (KCSAcinar) reveals a distinct cystic lesion lined by cuboidal or flattened epithelium with large irregular and hyperchromatic nuclei and absence of mucin-producing cells. Mice lacking Sox4 showed a significant reduction in the number of tuft cells. Furthermore, we observed an extensive reduction of the tumor stroma surrounding epithelial acinar-derived lesions in KCSAcinar compared to KC littermates. Next, we perform gene expression analysis of lesions 21 days after the induction of pancreatitis. Principal component analysis clusters the samples according to the genotype. Differential gene expression validated our histopathological analysis and showed a significant reduction in the expression of mucins and tuft cell markers. Cumulative, our data suggest that Sox4 is necessary for the specification of cellular states in the precursor lesions of PDAC, and that the cellular state of the tumor cell of origin determines the characteristics and cellular composition of the tumor microenvironment. Our work will continue to unravel the function of Sox4 in cancer initiation and the interaction of signaling pathways activated in pancreas regeneration with Kras mutations.