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VanSaun Lab

Adipokine Regulation of Pancreatic Cancer Progression

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Investigator / Contact Person Michael VanSaun

Research

The epidemic of obesity is a significant risk factor associated with 40% of all cancers, including pancreatic cancer that ranks as the third deadliest cancer with an approximate 9% 5 yr survival rate. Obesity associated inflammation incites a yin/yang dysregulation of adipose secreted cytokines, known as adipokines, whereby pro-tumorigenic adipokine (leptin, IL-6 and IL-1) levels increase and anti-tumorigenic adipokine (adiponectin) levels decrease. This dysregulation results in enhanced activation of mitogenic pathways, such as KRAS, that drive cancer progression and promote the recruitment of innate inflammatory cells. The inability to develop durable treatments for pancreatic cancer has been significantly impacted due to a failure to target oncogenic KRAS and the ineffectiveness of checkpoint inhibitors due to its immunosuppressive microenvironment. Our research shows that adiponectin is a critical negative regulator of obesity associated PDAC progression and provides a novel therapeutic strategy for the treatment of PDAC.

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 effectively suppresses tumor immune cell infiltration by inhibiting the secretion of pro-inflammatory attractants from tumor cells. Our results validate that adiponectin functions as a critical negative regulator of obesity associated PDAC progression by antagonizing pro-tumorigenic RAS activity as well as tumor driven inflammatory cell recruitment to overcome the innate resistance of PDAC.
The goal of our laboratory is to demonstrate that counteracting pro-tumorigenic adipokines can inhibit PDAC progression.

We currently have three main projects:

1.) We are using adiponectin deficient mice that have been crossed to genetic models of PDAC in order to determine how loss of adiponectin effects early initiation as well as late metastatic events in obesity driven PDAC. Additionally, we are testing whether adiponectin supplementation can counteract the pro-tumorigenic mechanisms of obesity.

2.)  We are deleting components of receptor tyrosine kinase signaling using either CRISPR or target specific inhibitors to elucidate how adiponectin suppresses pERK as well as pSTAT3 activation. 

3.) We have discovered that adipokines can stimulate cancer cells to secrete pro-inflammatory cytokines. To elucidate mechanisms of adipose-tumor crosstalk, we are using novel co-cultures and co-implant models to measure cytokine release and immune recruitment to the tumor microenvironment.

The outcome of our projects will yield significant new knowledge regarding the mechanisms governing obesity dependent cancer risk and progression. Further, our studies will uncover potential therapeutic uses for adiponectin receptor agonists in PDAC.