Determining how cancer cachexia influences gluconeogenesis

/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating and lethal disease associated with peripheral tissue wasting that is seen in most patients. This progressive wasting condition affecting skeletal muscle as well as fat and other tissues is referred to as cancer cachexia. PDAC patients with cancer cachexia have lower median survival than patients without cancer cachexia. There are currently no approved treatments for this disorder, including nutritional interventions. The Vander Heiden lab in a previous publication identified that the autochthonous mouse model of PDAC driven by KRAS activation with p53 deletion in the acinar cells of the pancreas was sufficient to drive cancer cachexia-induced muscle atrophy. These mice exhibited pancreatic enzyme insufficiency that was identified by the abundance of amino acids and fatty acids within the stools of cachexic KPC mice, indicating a lack of nutrient absorption. One of the key questions unanswered in the cancer cachexia field is whether the process of cancer cachexia serves to supply nutrients to the tumor to help it grow or it functions to help preserve the host. It is unknown where amino acids released from protein degradation in the muscle are going and what their purpose is. One of the organs in the body that requires an abundance of amino acids is the liver, as amino acids can be used to fuel gluconeogenesis. The rate-limiting enzyme for gluconeogenesis is phosphoenolpyruvate carboxykinase (PEPCK), which is upregulated in cancer cachexia by the IL6/JAK/STAT pathway in the liver. Therefore, we hypothesize that IL6/JAK/STAT signaling induces PEPCK and gluconeogenesis in the liver to promote cancer cachexia in primary and metastatic PDAC tumors. I will test this hypothesis in aim 1 by determining the contribution of PEPCK and gluconeogenesis in the liver to cancer cachexia and vice versa. Then in aim 2, I will study the role of IL6/JAK/STAT signaling on gluconeogenesis and metabolism in the livers of cachexic mice. Then in aim 3, I will determine whether cancer metastasis accelerates cachexia through promoting gluconeogenesis. The outcomes of this study will improve our understanding of whole-body metabolism and has therapeutic potential to facilitate the development of drug targets for cancer cachexia and/or PDAC. Project Number: 1K99CA300496-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Yichi Zhang | Institution: MASSACHUSETTS INSTITUTE OF TECHNOLOGY, CAMBRIDGE, MA | Award Amount: $133,955 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZCA1 RTRB-U (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11117687