Abstract C094: Tff2 defines pancreatic TA progenitors that are protective against Kras-driven carcinogenesis
Authors: Wu Feijing , Jiang Zhengyu , Zhi Xiaofei , Ochiai Yosuke , White Ruth A. , Malagola Ermanno , Qian Jin , Zheng Biyun , Tu Ruhong , Kobayashi Hiroki , Waterbury Quin , Zamechek Leah B. , Wang Timothy C. 
Published: January 2024

Abstract
Background: Progenitor or stem cells play a pivotal role in maintaining tissue homeostasis and are often the source of tumor progression. While genuine stem cells are absent in the pancreatic exocrine organ, a variety of progenitor cells are present that contribute to normal homeostasis and regeneration process post-injury. In a previous study, we identified a pancreatic facultative progenitor (FP) that was marked by the gene doublecortin kinase like-1 (Dclk1). These Dclk1+ FP are rare, long-lived, quiescent cells that are critical for regeneration following injury. In contrast, cells marked by Trefoil factor 2 (Tff2) are active progenitors within the gastrointestinal tract, playing a crucial role in homeostasis and tumor progression. However, the role of Tff2+ cells within the pancreas remains relatively underexplored. Method & Results: To explore the function of Tff2 cells, we developed a Tff2 BAC transgenic mouse line (Tff2-DTR-CreERT2), which was then crossed with report mice. Employing lineage tracing and single cell RNA sequencing, we uncovered a new type of progenitor, distinct from the FP - Tff2+ transit amplifying progenitors (TAP). Tff2+ acinar cells showed much greater proliferation (&gt;100-fold) than all other acinar cells. Single cell RNA-seq of the Tff2-expressing lineage showed that one cluster (cluster 0) identified acinar cells with a low differentiated, progenitor-like state. These cells were found to contribute to tissue homeostasis, exhibiting expansion in the early stages, giving rise to more differentiated acinar cells, peaking around six months, and then gradually diminishing until they disappeared. To understand the role of Tff2 in PanIN lesions, we developed a compound mouse model: Tff2-DTR-CreERT; Mist1-CreERT; KrasG12D(TMK). When Tff2+ cells were then ablated using Diphtheria Toxin in the setting of caerulein-induced pancreatitis, the TMK mice developed significantly more PanIN lesions. Tff2-CreERT; KrasG12D mice were generally more resistant to developing advanced PanINs, but in the setting of caerulein pancreatitis, the Tff2; KrasG12D model developed more pancreatic ductal adenocarcinoma (PDAC). To explore the role of the TFF2 peptide in tumor progression, we used an adenovirus expressing TFF2 (Ad-TFF2), and introduced it through tail vein injections. We found that Ad-Tff2 helped prevent the development of advanced PanIN lesions. Conclusion: In summary, our research indicated that Tff2 cells play a significant role in maintaining pancreatic homeostasis and act in paracrine fashion to suppress the development of pancreatic adenocarcinoma.
Citation Format: Feijing Wu, Zhengyu Jiang, Xiaofei Zhi, Yosuke Ochiai, Ruth A. White, Ermanno Malagola, Jin Qian, Biyun Zheng, Ruhong Tu, Hiroki Kobayashi, Quin Waterbury, Leah B. Zamechek, Timothy C. Wang. Tff2 defines pancreatic TA progenitors that are protective against Kras-driven carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C094.