Abstract 898: Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy
Authors: Incio Joao , Suboj Priya , Chin Shan M. , Ivy Chen , Ng Mei , Nia Hadi , Grahovac Jelena , Liu Hao , Kao Shannon , Babykutty Suboj , Huang Yuhui , Jung Keehoon , Rahbari Nuh , Han Xiaoxing , Chauhan Vikash , Martin John , Kahn Julia , Huang Peigen , Soares Raquel , Boucher Yves , Fukumura Dai , Jain Rakesh 
Published: July 2016

Abstract
INTRODUCTION: With the current epidemic of obesity, the majority of pancreatic cancer patients are overweight or obese at diagnosis. Importantly, obesity worsens treatment outcomes in pancreatic cancer patients. Therefore, understanding the mechanisms that underlie the poorer prognosis of obese cancer patients is of paramount importance. Obesity causes inflammation and fibrosis in the normal pancreas due to the accumulation of dysfunctional hypertrophic adipocytes. Importantly, desmoplasia - a fibroinflammatory microenvironment - is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and we have shown that activation of pancreatic stellate cells (PSCs) via angiotensin-II type 1 receptor (AT1) pathway is a major contribution to tumor desmoplasia. Whether obesity affects desmoplasia in PDACs, and interferes with delivery and response of chemotherapeutics is currently unknown.
EXPERIMENTAL DESIGN: Using both human samples and mouse models of PDAC - multiple syngeneic models of PDAC: PAN02, AK4.4, KPC, iKRAS in diet-induced and genetic obese mouse models -, we determined the effects of obesity on desmoplasia and inflammation/immune cell infiltration, tumor growth and delivery and response to chemotherapy.
RESULTS: We found that obesity aggravates desmoplasia in PDACs in both patient samples and multiple mouse models. In addition, tumors in obese mice presented with elevated levels of activated PSCs and fibrosis, as well as inflammatory cytokines and TANs,. These alterations in the tumor microenvironment in obesity associated with accelerated tumor growth, reduced tumor blood perfusion and increased hypoxia, and impaired delivery and efficacy of chemotherapeutics. Genetic ablation and pharmacological inhibition (losartan) of AT1 signaling reversed obesity-augmented desmoplasia and tumor growth, and improved the response to chemotherapy to the level observed in lean mice. We further discovered the underlying mechanisms: 1) obesity increases intra-tumor adipocytes and IL-1ß secretion by these cells; 2) increased IL-1ß induces TAN recruitment; 3) recruited TANs activate PSCs; and 4) activated PSCs enhance desmoplasia. Conversely, activated PSCs also secrete IL-1ß that recruits further TANs. Of clinical relevance, we found that metformin not only normalizes the abnormal systemic metabolism, but also reprogramms PSCs and immune cells and alleviates the fibroinflammatory microenvironment in pancreatic cancer in obesity/diabetes.. Importantly, the strategies described above were not effective in the normal weight setting.
CONCLUSION: Here we successfully demonstrated that targeting desmoplasia, including immunomodulation with anti-IL-1ß, or treatment with generic drugs such as losartan and metformin are potential strategies to potentiate treatments in PDAC patients with excess weight.
Citation Format: Joao Incio, Priya Suboj, Shan M. Chin, Chen Ivy, Mei Ng, Hadi Nia, Jelena Grahovac, Hao Liu, Shannon Kao, Suboj Babykutty, Yuhui Huang, Keehoon Jung, Nuh Rahbari, Xiaoxing Han, Vikash Chauhan, John Martin, Julia Kahn, Peigen Huang, Raquel Soares, Yves Boucher, Dai Fukumura, Rakesh Jain. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 898.