Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions

Abstract

SUMMARY The development of pancreatic cancer requires the acquisition of oncogenic Kras mutations and up-regulation of growth factor signaling, but the relationship between these is not well established. We here show that mutant Kras alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase Protein Kinase D1 and the transcription factors NF-κB1 and NF-κB2, which up-regulate expression of the epidermal growth factor, its ligands and their sheddase ADAM17. In vivo, intercepting Kras-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic Kras interacts with growth factor signaling to induce the formation of pancreatic cancer.

Extracellular vesicles swarm the cancer microenvironment: from tumor–stroma communication to drug intervention

“…During PanIN de-differentiation KRAS mutations in acinar cells have been shown to drive PKD1-dependent mitochondrial ROS increases and that this event is the leading factor responsible for EGFR-mediated ADAM17 shedding 43 . Similarly, in KRAS mutant colorectal cancer, inhibition of the PI3K/mTOR pathway sensitizes cells to EGFR inhibitors 8 .…”

KRas, ROS and the initiation of pancreatic cancer

“…1 Approximately 95% of all pancreatic ductal adenocarcinoma (PDA) show acquisition of activating KRAS mutations, 2 which, due to oncogene-mediated alterations in the cell's metabolism, goes along with increased cellular oxidative stress levels. [3][4][5][6] In mouse models for development of PDA, KRas-caused formation of ROS already is induced in acinar cells and gradually increased during ADM and PanIN formation and progression 5 (Fig. 1).…”

“…These include activation of the ERK1/2 signaling pathway, 6 upregulation of epidermal growth factor receptor (EGF-R) signaling, 5 as well as induction of canonical and alternative activation pathways for nuclear factor k-B (NF-kB), 5 which both have been implicated in the progression of PDA. 20,21 The serine/threonine kinase Protein Kinase D1 (PKD1) is a major mediator of KRas-mROS signaling, 5,22 however, its activation by mROS most likely is indirect. Previously, it was shown that in response to mROS PKD1 can be activated via Src-mediated phosphorylation…”

“…Typical metabolic changes initiated by tumor cells are, for example, an increase in aerobic glycolysis (Warburg effect) to support growth under hypoxic conditions 7 or altered mitochondrial metabolic activity. 5,6,[8][9][10] Oncogenic KRas can modulate mitochondrial metabolism and ROS generation by regulating hypoxia-inducible factors (HIFs) HIF-1a and HIF-2a, 8 or through regulation of the transferrin receptor (TfR1), which is highly expressed in pancreatic cancers. 11 In addition, KRas can induce suppression of respiratory chain complex I and III to cause mitochondrial dysfunction.…”

“…6,12 Decreased mitochondrial efficiency then results in an increased production of ROS. 5 A possible cause is the ROS-mediated occurrence of 4-hydroxy-2-nonenal (4HNE) and 4HNE-adduct formation with macromolecules, which can lead to inhibition of mitochondrial proteins or damage of mtDNA. 5 KRas-induced increases in intracellular ROS levels can also occur via altered NADPH oxidase activities, 1 i.e.…”