Prostate cancer (PCa) is the leading cancer diagnosis, and the second-leading cause of death among men in the United States. It affects 1 in 6 men, with more than 65% of all prostate cancers diagnosed in men over the age of 65. Based on this high prevalence and mortality, a major challenge for PCa research is to learn how to block progression of PCa in patients with more advanced or aggressive disease. In this regard, recent research suggests that obesity and excess weight can play a prominent role in the incidence and progression of various types of cancer. Of special relevance for this proposal, there is increasing evidence suggesting a link between obesity and increased risk of PCa, especially to more aggressive, fatal disease. Several studies have shown more adverse pathological features and higher risk for biochemical recurrence in obese men undergoing radical prostatectomy. In addition, obesity has also been associated with increased risk of progression to castration-resistant PCa, development of metastases, and, consequently, PCa-specific mortality. Likewise, more strong epidemiological associations with aggressive PCa have been found in studies that, in addition to using body mass index as a measure of obesity, also consider the amount of visceral fat or fat that surrounds the prostate (periprostatic fat). That is, higher visceral and periprostatic fat correlates with greater tumor aggressiveness in PCa patients. Given the current obesity epidemic and an aging population more prone to develop both PCa and obesity, there is an urgent need to explore potential interventions to break the obesity-cancer link, especially in patients at risk for PCa progression to fatal disease and recurrence.

Collectively, all these epidemiological studies support a role for obesity and weight gain as important risk factors for poor outcome in men diagnosed with PCa, but there are still many knowledge gaps that need to be addressed to understand the molecular mechanisms underlying this correlation. In this regard, accumulating evidence suggests that inflammation could be a critical player in the pathogenesis of obesity-related metabolic syndrome and in obesity-mediated PCa progression. Excess adipose (fat) tissue is associated with increased levels of pro-inflammatory cytokines that could be a major driver of PCa progression. In fact, it is now well established that adipose tissue serves not only as an energy storage compartment, but also as an endocrine organ with a key role in the coordination of systemic metabolism. In addition to this systemic function, adipocytes (fat cells) can modulate the tumor microenvironment. That is, depending on the proximity of tumor cells to fat depots, adipocytes can modify interactions with other supporting host cells. In addition, adipocytes may modulate the homing of tumor cells through adipokine secretion and may provide fuel and an inflammatory environment to favor tumor growth. This is important in cancers that are located in sites close to adipocyte-rich environments, like PCa. Interestingly, periprostatic fat correlates with tumor aggressiveness in PCa patients. This suggests a specific role for local adipocyte-tumor cell interactions in orchestrating a pro-inflammatory environment to promote tumor progression.

This proposal will focus on adipocyte-tumor cell interactions to learn how obesity, and the related inflammation, influences PCa progression by modifying the tumor microenvironment. We will profit from a novel and relevant in vivo mouse model discovered as part of the collaboration between our laboratories. We have identified the gene p62 as a novel player in PCa and in obesity-induced inflammation and have generated mice with this gene selectively eliminated in the adipose tissue. Interestingly, these mice with no p62 in the adipose tissue develop obesity and insulin resistance, as well as hyperinflammation in their fat. We will cross these mice with a model of PCa to investigate how the development of obesity and inflammation in these mice influences PCa progression. This mouse model will provide us with the unique opportunity to investigate the role of obesity in PCa from a genetic angle, independent of dietary factors. That is, p62 ablation results in obesity even under normal diet conditions, and without changes in calorie intake. This is very important because it suggests that patients with low levels of p62 would be unresponsive to reduced calorie intake as a way to control obesity and therefore the progression of PCa. We will carry out a complete characterization of the metabolic and inflammatory phenotype in the prostate as well as in the different fat depots, such as periprostatic fat. In addition, we will perform a parallel molecular study on the development and progression of PCa in these mice. This project has the potential to identify the molecular mechanisms by which obesity influences PCa. Understanding this process is an essential step towards new strategies to therapeutically intervene in PCa. Interfering with adipocyte-tumor cell interactions to disrupt PCa progression could be a much-needed new therapeutic avenue to break the obesity-cancer link, an urgent matter that is reaching epidemic proportions.