The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
Goldman, O., Adler, N., L. et al. Cancer Discovery. 13 (7): 1616–1635. (2023).
doi: 10.1158/2159-8290.CD-22-1062.
Summary of the findings
The liver is a major metabolic and immunological organ that preserves systemic homeostasis under stress. Goldman, Adler, and colleagues describe the involvement of liver metabolism in extrahepatic tumor growth and progression. Following cancer-induced systemic inflammation, they find that innate immune cells are recruited to the liver by CCL2. The resulting interactions lead to activation of Erk, secretion of IL-6 from immune cells, and initiation of STAT3 signaling in hepatocytes. Consequently, there is an almost complete loss of HNF4α, the master regulator of liver metabolism. Loss of HNF4α perturbs the function of central liver metabolic pathways such as the urea cycle, albumin, and fatty acid synthesis, increasing plasma availability of nitrogen-rich metabolites such as ammonia, glutamate, and aspartate, promoting tumor growth. Notably, the high ammonia levels inhibit lymphocyte proliferation and activation, further empowering cancer cells’ survival. In addition, the dysregulation of albumin and fatty acid synthesis likely contributes to cancer progression to systemic manifestations such as weight loss. Indeed, maintaining HNF4α using a viral vector preserves liver metabolism, alleviates fat and muscle loss and weight loss, and increases survival in a pancreatic cancer mouse model. Significantly, scoring the biochemical liver profile in breast and pancreatic cancer patients can predict weight loss.
Future impact
Cancer-associated cachexia manifestations such as weight loss do not efficiently respond to therapy or a high-calorie diet. The findings described here have impactful clinical implications, as they offer an opportunity for early intervention by providing a liver biochemical score that identifies patients at risk for weight loss in breast and pancreatic cancer patients on the day of diagnosis. Additionally, the findings demonstrate that maintaining liver expression of HNF4α, preserves liver metabolism and can effectively alleviate weight loss in cancer mouse models. Notably, the results highlight the importance of understanding the tumor MACRO-environment for benefiting cancer diagnosis and therapy.
Summary of the findings
