Haoyu Tang, Bethsebie Sailo, Xingbo Shang, Md Shahadat Hossan, Jeremy Kratz, Paromita Das, Ankit Chhoda, Paulomi Aldo, He Liu, Marie E Robert, Saryn Doucette, Timothy J Paris, John W Kunstman, Emmanouil Pappou, Laura D Wood, Christine A Iacobuzio-Donahue, Christopher L Wolfgang, Mariateresa Mazzetto, Linda He, Marie Pfaff, Olivia Ang-Olson, Timothy Hoggard, Rolando Garcia-Milian, Anup Sharma, Andre Levchenko, Nita Ahuja
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with increasing incidence and a dismal prognosis. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of PDAC progression with a previously unrecognized role in epigenomic regulation. We show that SPINK1 expression, which is highly dynamic across PDAC progression, is associated with key aggressive cancer phenotypic states and regulates cancer cell stemness and plasticity in both in vitro and patient samples. Mechanistically, our results suggest a new signaling axis where SPINK1 interacts with COL18A1 to promote its cleavage into endostatin, which then induces histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and highlight the SPINK1-COL18A1-endostatin signaling axis as a potential therapeutic target to combat PDAC aggressiveness.