Abstract Pancreatic cancer remains one of the leading causes of cancer-related mortality worldwide, with its incidence more than doubling over the past 25 years. Approximately 10% of cases are hereditary, linked to specific inherited genetic factors. Among these, germline mutations in the tumor suppressor gene LKB1/STK11, associated with the inherited cancer disorder Peutz-Jeghers Syndrome, confer an exceptionally high risk, over a 100-fold increase for developing pancreatic cancer. Beyond its hereditary implications, analysis of human pancreatic tumors reveals that around 20% exhibit downregulation of LKB1 compared to normal ductal epithelium. This downregulation of LKB1 is associated with advanced-stage disease, increased metastasis, and reduced overall survival. Despite these clinical associations, the functional role of LKB1 in pancreatic tumorigenesis remains poorly defined. To address this, we employed genetically engineered mouse models to demonstrate that loss of LKB1 significantly increases tumor burden and shortens survival, supporting its tumor-suppressive function. We further explored the roles of LKB1 substrates - SIK kinases and AMPK - and found distinct contributions to tumorigenesis, with unique phenotypic and histopathological features compared to each other and to LKB1 loss. To uncover the molecular mechanisms underlying these effects, we performed single-cell RNA sequencing (scRNA-seq) on tumors from these models. This analysis revealed both shared and unique transcriptional programs triggered by the loss of LKB1 and its downstream effectors, alongside extensive remodeling of the tumor microenvironment. Together, our in vivo models and scRNA-seq dataset offer insight into the cancer-intrinsic and -extrinsic processes driven by LKB1 loss and provide a foundation for identifying potential therapeutic targets in LKB1-deficient pancreatic cancer. Citation Format: Shira Yomtoubian, Reuben Shaw, Danielle Engle, Kristina Peck, April Wehner, Jingting Yu. Investigating the role of LKB1/STK11 in pancreatic cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A033.
Yomtoubian et al. (Sun,) studied this question.