Study Evaluates Obesity-Related Factors Leading to Pancreatic Cancer Progression Interview with:

Joao Incio MD Research Fellow in Radiation Oncology Harvard Medical School/MGH Boston, MA

Dr. Joao Incio

Joao Incio MD
Research Fellow in Radiation Oncology
Harvard Medical School/MGH
Boston, MA What is the background for this study?

Dr. Incio: 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, was the focus of our study. What are the main findings?

Dr. Incio: 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 tumor-associated neutrofils (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 reprograms 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. What should clinicians and patients take away from your report?

Dr. Incio: 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. Prospective studies with these drugs are warranted. What recommendations do you have for future research as a result of this study?

Dr. Incio: Additional pharmacological agents that target the obesity-related factors should be evaluated. In addition, it appears that obesity causes immunosupression in the microenvironment, therefore immunotherapy may also be a possible intervention to prevent obesity-induced tumor progression.

Citation: AACR Abstract Apr 17, 2016,

Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy
Joao Incio1, Priya Suboj1, Shan M. Chin1, Chen Ivy1, Mei Ng1, Hadi Nia1, Jelena Grahovac1, Hao Liu1, Shannon Kao1, Suboj Babykutty1, Yuhui Huang1, Keehoon Jung1, Nuh Rahbari1, Xiaoxing Han1, Vikash Chauhan1, John Martin1, Julia Kahn1, Peigen Huang1, Raquel Soares2, Yves Boucher1, Dai Fukumura1, Rakesh Jain1. 1Harvard Medical School/MGH, Boston, MA; 2FMUP, Portugal