Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) mutations have been considered a critical driver of PDAC initiation and progression. However, the effects of mutant KRAS alone do not recapitulate the full spectrum of pancreatic pathologies associated with PDAC development in adults. Historically, mutant KRAS was regarded as constitutively active; however, recent studies have shown that endogenous levels of mutant KRAS are not constitutively fully active and its activity is still subject to up-regulation by upstream stimuli. Obesity is a metabolic disease that induces a chronic, low-grade inflammation called meta-inflammation and has long been recognized clinically as a major modifiable risk factor for pancreatic cancer. It has been shown in different animal models that obesogenic high-fat diet (HFD) and pancreatic inflammation promote the rapid development of mutant KRAS-mediated PDAC with high penetrance. However, it is not clear why the pancreas with endogenous levels of mutant KRAS is vulnerable to chronic HFD and inflammatory challenges. Recently, the discovery of fibroblast growth factor 21 (FGF21) as a novel anti-obesity and anti-inflammatory factor and as a downstream target of mutant KRAS has shed new light on this problem. This review is intended to provide an update on our knowledge of the vulnerability of the pancreas to KRAS-mediated invasive PDAC in the context of challenges engendered by obesity and associated inflammation.

The Intricate Crosstalk Between Insulin and Pancreatic Ductal Adenocarcinoma: A Review From Clinical to Molecular

“…Moreover, insulin promotes adipocytes proliferation by stimulating the expression of several factors such as neuropeptide Y ( Yang et al, 2008 ). Under the stimulation of insulin, pancreatic fat consistently secretes inflammatory factors such as IL-6, TNF to alter chronic inflammation in the pancreas, which finally leads to oncogenic mutation and the onset of PDA ( Klöting and Blüher, 2014 ; Murphy et al, 2018 ; Brocco et al, 2020 ; Luo et al, 2021 ). Despite inducing inflammation, the oncogenic mutation can be maintained by insulin in pancreatic precursor lesions ( Zhang et al, 2019 ).…”

Obesity and Pancreatic Cancer: Insight into Mechanisms

“…On target cells, FGF21 binds to and activates a receptor complex of FGF receptor 1c (FGFR1c) and its co-receptor β-Klotho (KLB); however, little is known about the downstream intracellular signaling events [143]. Exciting recent studies implicate FGF21 in obesity-promoted PDAC [147][148][149]. Lu and colleagues reported that FGF21, its target receptor FGF receptor 1 (FGFR1), and its coreceptor β-Klotho (KLB) were expressed in normal pancreatic acinar cells and showed that FGF21 levels were decreased downstream of oncogenic Kras [147].…”

Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities

“…Inflammation is the most established environmental factor that propels KRAS-induced neoplastic progression in PDAC. In human patients, KRAS mutations are detected in >90% of early staged pre-cancerous pancreatic intraepithelial neoplasias (PanINs) [26], but transformation to full-blown cancer occurs at a very low incidence, and is more much likely in patients with chronic pancreatitis or obesity, conditions which are associated with chronic systemic inflammation [27][28][29]. This association is well recapitulated in genetically engineered mouse models (GEMMs), in which pancreas-specific expression of oncogenic KRAS (KRAS G12D ) alone is highly inefficient in inducing PanINs or PDAC, predominantly due to oncogene-induced cellular senescence [30,31].…”

“…Obesity is an important clinical factor that drives engagement of the TIR receptors, mainly via increased intra-tumoral cytokines and possibly enhanced translocation of gut microbes. Various preclinical studies showed that obesity accelerates progression to PDAC in KRAS G12D -mutant GEMMs [28,72,73]. Mechanistically, adipocytes produce various inflammatory cytokines including IL-1α, IL-1β, TNF, and IL-6 [29,74], leading to production of more of these cytokines by PDAC cells and pancreatic stellate cells, ultimately drawing in inflammatory myeloid cells which aggravate intra-tumoral inflammation.…”