Pancreatic cancer-associated cachexia as a 3-stage systemic disease with changes in body composition, tissue-specific wasting across time and alterations in glucose metabolism.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that rapidly deteriorates the organism resulting in <10% 5-years survival in humans. Cancer-associated cachexia (CAC) is a multi-organ complex syndrome that accompanies PDAC in 85% of the cases. CAC is often characterized by the loss of body weight, including loss of muscle and fat tissues. Chronic inflammation, myokines and adipokines (released from muscle and fat, respectively), together with few recent tumor-derived factors, have been shown to collectively induce some of the metabolic changes in peripheral tissues that lead to wasting. Those include the synthesis of acute phase proteins in the liver, lipolysis and browning of the white adipose tissues (WAT), and protein degradation in the skeletal muscle. However, how these changes affect systemic metabolism, such as amino-acid utilization for liver gluconeogenesis, the systemic consequences of increased free fatty acids from lipolysis and their final destination for b-oxidation, or the rewiring of glucose metabolism, are processes not fully understood during cachexia. Here we established a 3-stage model of cachexia progression, including pre-, early- and late-CAC stages, in a doxycycline inducible murine model of PDAC (p48(Cre/+);tetKRAS(LSL/+);p53(fl/fl)), in both genders. We have monitored body weight loss, changes in body composition using DEXA scan, food intake and survival, across time since the start of doxycycline administration (i.e. tumor initiation). We have submitted these mice to metabolic cages aiming to distinguish in which of the 3 stages fat consumption starts, as well as monitored the weight of 8 tissue types (pancreas, liver, iWAT, eWAT, brown adipose tissue, quadriceps, gastrocnemius and soleus) over time. Overall, we have defined pre-CAC as “weight-gaining stage, before body weight peaks”, early-CAC as <10% and late-CAC as >10% of body weight loss, together with specific changes in body composition in each stage, food intake only happening at the very end stage, while all non-tumoral tissues present significant reduced weight at early stages. We have performed metabolomics and lipidomics in all peripheral tissues, aiming to identify changes that occur not only at early- but also at the pre-CAC stages, when pancreatic tumors already weighed more than double of the normal pancreas. In addition, glucose tolerance test analyses showed that tumor-bearing mice cleared the glucose more rapidly than control mice, even at pre-CAC stages, opening new avenues to continue studying glucose metabolism in the periphery such as increased liver gluconeogenesis and peripheral insulin resistance. Together, these results allowed us to establish a murine model to study cachexia in 3 stages, similar to what happens in humans. Furthermore, metabolomic data from the peripheral tissues, tumor interstitial fluid (TIF) and plasma, will allow us to identify the metabolic landscape of the entire organism throughout the progression of the disease, and potentially propose new therapeutic windows to target or prevent wasting in cancer. Citation Format: Blanca Majem, Insia Naqvi, Courtney Dennis, Lucas Dailey, Clary B. Clish, Nada Kalaany. Pancreatic cancer-associated cachexia as a 3-stage systemic disease with changes in body composition, tissue-specific wasting across time and alterations in glucose metabolism [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-029.