Maturity-onset diabetes of the young type 4 (MODY4) is a rare monogenic form of diabetes caused by PDX1 mutations. Evidence suggests that PDX1 downregulation or mutation contributes to diabetes phenotypes but also promotes pancreatic ductal adenocarcinoma (PDAC) progression. Generally, diabetes is both a risk factor and potential early sign of PDAC. However, the distinct role of monogenic diabetes types, e.g. MODY4, in PDAC remains unclear. This study aims to determine the role of PDX1 haploinsufficiency in a KRAS-driven mouse model of PDAC, helping to identify metabolic alterations as early PDAC indicators. Our findings may provide new insights into diabetes-driven cancer progression and help establish detection strategies for high-risk individuals.
Pdx1-Flp mice, expressing a flippase recombinase under the endogenous Pdx1 promoter, exhibit a pre-diabetic (MODY4-like) phenotype. Crossing Pdx1-Flp with FSF-KrasG12D mice generates a diabetic PDAC model. Alterations in glucose metabolism were assessed at 4 weeks, 8 weeks and the humane endpoint. Endocrine cells, tumor progression, stroma composition and invasion were analyzed by histology. Age- and sex-matched normoglycemic Pdx1-Cre;LSL-KrasG12D (KC) mice served as controls.
Unlike KC mice, Pdx1-Flp;FSF-KrasG12D (KF) mice exhibited low-grade neoplastic lesions already at 4 weeks of age. 8-week-old male KF mice displayed glucose intolerance, disturbed fasting blood glucose levels, and blunted glucose-stimulated insulin secretion. Female KF mice showed later onset of metabolic imbalances. KF mice exhibit loss of beta cell identity, enhanced fibrotic tumor stroma, increased invasiveness and liver metastasis, compared to KC mice. The rapid tumor onset and its aggressiveness ultimately led to substantially reduced survival, with strong sex-specific difference in KF (male vs. female median survival: 10w vs. 40w) but not the KC mice (median survival 93w vs. 87w).
This study utilizes a genetic model of PDX1 haploinsufficiency to investigate the unexplored link between MODY4 diabetes and pancreatic cancer. Unlike previous studies that rely on diet-induced diabetes models, our approach provides a physiologically relevant system to assess how PDX1 perturbation influences both glucose metabolism and tumor progression. By identifying potential metabolic shifts as early indicators of PDAC, our findings could contribute to the identification of biomarkers for early detection, addressing a critical gap in pancreatic cancer research.