The role of LIF in tissue homeostasis, disease, and cancer
Creators: name: Wang, Jianming
Publisher: name: No Publisher Supplied
Year: 2022

description: Part I: LIF is essential for ISC function and protects against radiation-induced gastrointestinal syndromeLeukemia inhibitory factor (LIF) is a cytokine essential for maintaining pluripotency of mouse embryonic stem cells. However, its role in adult intestinal stem cells (ISCs) is unclear. The adult intestinal epithelium has a high self-renewal rate driven by ISCs in crypts. Here, we find that LIF is present in the ISC niche in crypts and critical for the function of ISCs in maintaining the intestinal epithelial homeostasis and regeneration. Mechanistically, LIF maintains β-catenin activity through the AKT/GSK3β signaling to regulate ISC functions. LIF deficiency in mice impairs the renewal of the intestinal epithelium under the physiological condition. Further, LIF deficiency in mice impairs the regeneration of intestinal epithelium in response to radiation and shortens the lifespan of mice after high doses of radiation due to gastrointestinal (GI) syndrome, which can be rescued by administering recombinant LIF (rLIF). Importantly, LIF exhibits a radioprotective role in wild-type (WT) mice by protecting mice from lethal radiation-induced GI syndrome; administering rLIF promotes intestinal epithelial regeneration and prolongs survival in WT mice after radiation. These results reveal a previously unidentified and a crucial role of LIF in ensuring ISC function, promoting regeneration of the intestinal epithelium in response to radiation and protecting against radiation-induced GI syndrome.Part II: LIF protects against GVHD while preserving GVL activityGraft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation, a widely-used therapy for hematologic malignancies and blood disorders. Here, we report an unexpected role of cytokine LIF in protecting against GVHD development. Administrating rLIF protects mice from GVHD-induced tissue damage and lethality without compromising the graft-versus-leukemia (GVL) activity, which is crucial to prevent tumor relapse. We found that rLIF reduces donor immune cell infiltration and activation, and protects ISCs to ameliorate GVHD. Mechanistically, rLIF downregulates IL12-p40 expression in recipient dendritic cells (DCs) post irradiation through activating the STAT1 signaling, which results in decreased MHC-II levels on intestinal epithelial cells and reduced donor T cell activation and infiltration. This study reveals a previously unidentified protective role of LIF for GVHD-induced tissue pathology and provides a potential effective therapeutic strategy to limit tissue pathology without loss of anti-leukemic efficacy.Part III: LIF drives glucose metabolic reprogramming to promote breast tumorigenesisLIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.