Abstract A45: Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy
Authors: Incio Joao , Liu Hao , Suboj Priya , Min Shan , Chen Ivy , Ng Mei , Nia Hadi , Grahovac Jelena , Kao Shannon , Babykutty Suboj , Huang Yuhui , Jung Keehoon , Rahbari Nuh , Han Xiaoxing , Chauhan Vikash , Martin John , Kahn Julia , Huang Peigen , Deshpande Vikram , Michaelson James , Ferrone Cristina , Soares Raquel , Boucher Yves , Fukumura Dai , Jain Rakesh 
Published: March 2017

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 fibro-inflammatory 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 inflammation, PSCs and desmoplasia in PDACs, and interferes with delivery and response of chemotherapeutics is currently unknown.
Experimental Design: Using 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, tumor growth and delivery and response to chemotherapy. We further evaluated whether the obesity-induced effects were mediated by AT1 signaling as well as via immune cell recruitment, and dissected the crosstalk between PSCs, cancer-associated adipocytes (CAAs), and tumor-associated neutrophils (TANs). In addition, we determined if an anti-diabetic drug metformin could counter these effects in vivo, and further dissected the mechanism of action in vitro.
Results: We found that obesity aggravates desmoplasia in PDACs in 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. Hence, inactivation of PSCs through AT1 blockade resulted in not only decreased fibrosis but also reduced IL-1ß level and TAN recruitment. Furthermore, reduction of either TANs, IL-1ß, or PSC activation reduced tumor growth in obese mice. These findings suggest that crosstalk between adipocytes, immune cells, and PSCs exacerbates desmoplasia and promotes tumor progression during obesity. Of clinical relevance, we found that metformin not only normalizes the abnormal systemic metabolism, but also alleviates the fibro-inflammatory microenvironment in pancreatic cancer in obesity/diabetes. This occurred via direct reprogramming of PSCs and immune cells by metformin. 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. With a better understanding of the mechanisms by which obesity promotes tumor progression and therapy resistance, we will be able to improve the current standard of care in pancreatic cancer.
Citation Format: Joao Incio, Hao Liu, Priya Suboj, Shan Min, Ivy Chen, Mei Ng, Hadi Nia, Jelena Grahovac, Shannon Kao, Suboj Babykutty, Yuhui Huang, Keehoon Jung, Nuh Rahbari, Xiaoxing Han, Vikash Chauhan, John Martin, Julia Kahn, Peigen Huang, Vikram Deshpande, James Michaelson, Cristina Ferrone, 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 AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A45.