SPINK1-COL18A1 crosstalk shapes epigenome and drives cancer stemness in pancreatic ductal adenocarcinoma
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis. Discovery and mechanistic understanding of the genetic and epigenetic drivers of PDAC is therefore of critical importance. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of clinical progression and demonstrate that it can have a non-canonical function as a regulator of epigenomic states of PDAC cells and associated extensive changes in gene expression. We show that SPINK1 expression, which varies in PDAC, is associated with key aggressive phenotypic cancer states and is correlated with the expression of stemness markers both in vitro and in patient samples. Mechanistically, our results strongly suggest that SPINK1 acts through a new signaling axis, by interacting with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and suggest a potential therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling.
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Authors: 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
Institutions: Johns Hopkins University, Yale University, NYU Langone Health, New York University, Johns Hopkins Medicine, Sidney Kimmel Comprehensive Cancer Center, Mayo Clinic in Arizona, Memorial Sloan Kettering Cancer Center, Johns Hopkins Hospital, Systems Biology Institute, Yale Cancer Center