The role of Angiopoietin-like protein 4 in macrophage activation

Angiopoietin-like protein 4 (Angptl4) is a matricellular protein that associates with extracellular matrix proteins, mediating complex cell-cell, and cell-matrix interactions. It has been implicated in various inflammation-associated diseases, including atherosclerosis, pulmonary damage, and wound healing. Studies have shown Angptl4 to be a key regulator of wound healing, affecting different processes like cell adhesion, migration, and angiogenesis. However, very few reports describe a direct role for Angptl4 in immune cell development and response. Using single-cell RNA sequencing to examine the temporal changes in the immune cell landscape of excisional wounds from wild type and Angplt4-knockout (Angplt4-/-) mice revealed that Angptl4-/- wounds had a stalled inflammatory phase. We identified interferon activated protein 202B (ifi202b) to be consistently upregulated in Angptl4-/- macrophages. We confirmed that ifb202b significantly impacted multiple gene networks involved in the cell fate of monocytes and the functions of monocyte-derived macrophages. Taken altogether, we show the importance of Angptl4 in macrophage function during wound healing and its parallels to diabetic wounds during deficiency.Doctor of Philosoph

Targeting metabolic flexibility via angiopoietin-like 4 protein sensitizes metastatic cancer cells to chemotherapy drugs

Abstract Overcoming multidrug resistance has always been a major challenge in cancer treatment. Recent evidence suggested epithelial-mesenchymal transition plays a role in MDR, but the mechanism behind this link remains unclear. We found that the expression of multiple ABC transporters was elevated in concordance with an increased drug efflux in cancer cells during EMT. The metastasis-related angiopoietin-like 4 (ANGPTL4) elevates cellular ATP to transcriptionally upregulate ABC transporters expression via the Myc and NF-κB signaling pathways. ANGPTL4 deficiency reduced IC50 of anti-tumor drugs and enhanced apoptosis of cancer cells. In vivo suppression of ANGPTL4 led to higher accumulation of cisplatin-DNA adducts in primary and metastasized tumors, and a reduced metastatic tumor load. ANGPTL4 empowered cancer cells metabolic flexibility during EMT, securing ample cellular energy that fuels multiple ABC transporters to confer EMT-mediated chemoresistance. It suggests that metabolic strategies aimed at suppressing ABC transporters along with energy deprivation of EMT cancer cells may overcome drug resistance