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.

Keywords: FGF21; KRAS; PDAC; inflammation; obesity.

Figure 1

The activation of KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) under different physio-pathological conditions. (A). Under physiological conditions, the activity of wild-type KRAS GTPase (KRAS^wt) is tightly controlled by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), maintaining KRAS in an inactive KRAS^wt-guanosine diphosphate (GDP) state unless an upstream external signal stimulates GEFs, which in turn promote the loading of guanosine triphosphate (GTP) in place of GDP to KRAS and thus switch the inactive KRAS^wt-GDP state to active KRAS^wt-GTP state. When interacting with GAPs, the intrinsic GTPase activity of KRAS^wt is greatly accelerated, which hydrolyzes the active KRAS^wt-GTP to inactive KRAS^wt-GDP, leading to transient activation of KRAS. (B). Oncogenic mutations in KRAS (KRAS^mt) disrupt interactions with GAPs. However, these mutations neither alter the interactions with GEFs nor affect the intrinsic GTPase activity of KRAS and thus, KRAS^mt is still subject to GEF stimulation, potentially resulting in a prolonged KRAS^mt-GTP state and delayed inactivation to KRAS^mt-GDP. Such mutational activation of KRAS has been thought to drive mild inflammation, low-grade PanIN lesions, and spontaneous pancreatic ductal adenocarcinoma (PDAC) development when expressed at the embryonic stage or the early stage after birth. (C). Chronic high-fat diet (HFD) or pancreatic inflammation hyperactivates mutant KRAS, leading to extensive inflammation, high-grade PanIN lesions, and rapid PDAC development. GEF, guanine nucleotide exchange factor. GAP, GTPase activating protein. HFD, high-fat diet.

Figure 2

The mechanistic interplay of mutant KRAS and obesity/inflammation. Oncogenic KRAS not only directly or indirectly promotes cell proliferation, resistance to apoptosis, alteration of metabolism but also silences the expression of FGF21, a novel anti-obesity and anti-inflammation factor, leading to irreversible acinar-to-ductal metaplasia (ADM), fibrosis, and PanIN lesions. The loss of acinar cell FGF21 (and the alteration of other genes) by mutant KRAS promotes vulnerability in the acinar cell compartment to chronic HFD or inflammatory challenge, leading to KRAS hyperactivation, accentuated pancreatic inflammation, advanced PanIN lesions, and subsequent development of PDAC with high penetrance. Images were from the experiments of our laboratory.