The epidemic of obesity is a significant risk factor in five of the six most common forms of cancer, including
pancreatic ductal adenocarcinoma (PDAC). Inflammatory responses associated with obesity lead to the
dysregulation of adipose secreted cytokines, referred to as adipokines. In obese individuals, serum levels of
leptin, a pro-tumorigenic adipokine, dramatically increase while the anti-tumorigenic adiponectin levels decrease,
ultimately promoting cancer progression. Our efforts have shown that obesity induces adipocytes to increase
leptin and IL-6 secretion, which exert pro-tumorigenic effects in PDAC cells that drive proliferation, migration and
in vivo tumor growth. We have now identified that the anti-tumorigenic adipokine, adiponectin, counteracts the
effects of pro-tumorigenic adipokines in obesity associated PDAC progression through multiple mechanisms.
First, adiponectin antagonizes leptin and IL-6 induced activation of STAT3 and ERK signaling in PDAC cells
resulting in suppression of PDAC growth. Second, adiponectin blocks activation of the Src homology region 2
containing protein tyrosine phosphatase (SHP-2), a key mediator of leptin and IL-6-induced RAF-RAS-ERK
signaling. Third, adiponectin effectively inhibits the secretion of inflammatory cell attractants from tumor cells.
Our results validate that adiponectin is a critical negative regulator of obesity associated PDAC progression and
provide a novel therapeutic strategy for the treatment of PDAC.
The goal of this proposal is to determine whether counteracting adipose secreted cytokines can inhibit PDAC
progression. Our central hypothesis is that adiponectin overcomes innate resistance of PDAC by antagonizing
adipokine mediated RAS activity through suppression of SHP-2 and by blocking inflammatory cell recruitment
into the tumor microenvironment. The overall objective is to determine whether adiponectin represents a viable
therapeutic strategy to counteract obesity driven PDAC. This will be accomplished by the following specific aims:
Aim 1. Determine how adiponectin level effects obesity-induced PDAC progression. In this aim, we will
determine whether loss of adiponectin potentiates PDAC progression and whether adiponectin supplementation
can counteract the pro-tumorigenic mechanisms of obesity. Aim 2. Determine the effect of SHP-2 inhibition
on obesity driven PDAC development and progression. This aim will determine whether loss or inhibition of
the tyrosine phosphatase SHP-2 is sufficient to suppress obesity dependent PDAC progression. Aim 3.
Determine how adiponectin regulates recruitment of pro-tumorigenic immune cells to the tumor
microenvironment. Immune cell profiling will be used to investigate whether adiponectin can block the
production and/or secretion of inflammatory chemoattractants from PDAC cells to prevent immune cell
recruitment to the tumor microenvironment. The outcome of these specific aims will yield significant new
knowledge regarding the mechanisms governing obesity dependent cancer risk and progression. Further, these
studies will uncover potential therapeutic uses for adiponectin receptor agonists in PDAC.