Iacobuzio-Donahue, Christine A
Mayo Clinic
Department of Pathology, Memorial Sloan Kettering Cancer Center, 417 Est 68th Street New York, NY 10065, USA.
Citations 2
Evidence that extra copies of chromosome 1q play a role in the early phases of pancreatic neoplasia
Douville, Christopher, Parksong, Jeeun , Molin, Marco Dal, Graham, Sarah , Greipp, Patricia T. , Knudson, Ryan A., Curtis, Samuel , Wang, Yuxuan , Dobbyn, Lisa , Popoli, Maria , Ptak, Janine , Silliman, Natalie , Romans, Katharine , Iacobuzio-Donahue, Christine A., Makoohon-Moore, Alvin P., Goggins, Michael, Hruban, Ralph H., Kiemen, Ashley, Bettegowda, Chetan, Kinzler, Kenneth W., Papadopoulos, Nickolas, Wood, Laura D, Vogelstein, B., Goggins, Michael , Hruban, Ralph H. , Papadopoulos, Nickolas , Kinzler, Kenneth W. , Bettegowda, Chetan , Douville, Christopher , Iacobuzio–Donahue, Christine A. , Wang, Yuxuan , Wood, Laura D. , Molin, Marco Dal , Douville, Christopher , Dal Molin, Marco , Knudson, Ryan, Iacobuzio-Donahue, Christine A , Lennon, Anne Marie , Goggins, Michael G , Hruban, Ralph H , Kiemen, Ashley , Bettegowda, Chetan , Kinzler, Kenneth W , Papadopoulos, Nickolas , Wood, Laura D , Vogelstein, Bert , Ptak, Janine , Dobbyn, Lisa , Silliman, Natalie , Greipp, Patricia T , Vogelstein, Bert
Science Advances | February 20, 2026 | Volume: 12 | Issue: 8 | Pages: No page available
We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.
SPINK1-COL18A1 Crosstalk Shapes Epigenome and Drives Cancer Stemness in Pancreatic Ductal Adenocarcinoma
García-Milian, Rolando , Tang, Haoyu , Iacobuzio-Donahue, Christine A , Sailo, Bethsebie, Shang, Xingbo, Hossan, Md Shahadat , Kratz, Jeremy D. , Das, Paromita , Chhoda, Ankit , Aldo, Paulomi, Liu, He , Robert, Marie E. , Doucette, Saryn , Paris, Timothy J., Kunstman, John W. , Pappou, Emmanouil, Wood, Laura D. , Iacobuzio–Donahue, Christine A. , Wolfgang, Christopher L. , Mazzetto, Mariateresa , He, Linda, Pfaff, Marie, Hoggard, Timothy , Sharma, Anup, Levchenko, Andre , Ahuja, Nita
No container title available | March 7, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
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.