Tumor Cell-derived LIF and Gal3 Hijack Neural Signals to Promote Cancer Proliferation

Neural signals can significantly influence the prognosis of various cancer types. However, how tumor cells proactively modulate the nervous system to benefit their own survival remains incompletely understood. In this study, we report the multi-omic screening of mouse cancer models to identify leukemia inhibitory factor (LIF) and galectin-3 (Gal3) as the key tumor cell-derived factors that activate the central nervous system. Also, increased plasma levels of these two cytokines are commonly observed in patients of different cancer types. Of importance, LIF and Gal3 act cooperatively to trigger the paraventricular nucleus of the hypothalamus (PVN), the key brain region initiating efferent sympathetic signals. Further, we demonstrate that such tumor cell-triggered sympathetic signals dampen anticancer immunity, and enhance the tumor proliferating rate. Conversely, eliminating the tumor cell-derived LIF or Gal3 mitigates those effects and strongly inhibits cancer progression. These results have established a novel mechanism of tumor cells hijacking the body's nervous system to promote cancer proliferation.