Browsing by Author "Päivinen, Pekka"

Cancer-associated fibroblasts (CAF) form a heterogenous stromal cell population of a solid tumor. They are known to promote tumor growth and survival through metabolic reprogramming and inflammation. It is unclear though whether CAF are crucial component of tumor initiation and whether CAFs are dispensable altogether from the fully developed neoplasm. Tumor suppressor LKB1 regulates AMPK and AMPK-related kinases (ARK), and its function is compromised in familial disorder Peutz-Jeghers syndrome (PJS). Fibroblast specific haploinsufficiency of LKB1 alone is sufficient of initiating gastrointestinal polyposis but the mechanism through which LKB1 mediates this is only partially understood. We provide evidence that LKB1 is downregulated in multiple human malignancies including high grave serous ovarian cancer (HGSOC). Human ovarian cancer is the most lethal gynecological disease, characterized by metastasis of omentum. Loss-of LKB1 in ovarian fibroblasts was accompanied with metabolic changes associated with CAF-transformation. We screened down critical LKB1 substrates through transcriptomic and functional assays revealing AMPKa1 and MARK3 as potential downstream effectors of oxidative phosphorylation. AMPKa1, MARK1 and SIK-family were the glycolytic counterparts. We also took an initiative of cataloguing published human cancer stroma data in order to gain more comprehensive look of tumor heterogeneity. Metabolic rewiring was also observable in published cancer-stroma datasets. Human cancer-stroma divided into metabolically active and highly inflamed subtypes. These results highlights LKB1’s role as a conserved metabolic caretaker in fibroblasts. Our data also support mechanistic model in which LKB1 and ARKs regulate mitochondrial metabolism, essential for CAF transformation.