Paracrine signalling of AGR2 stimulates RhoA function in fibroblasts and modulates cell elongation and migration

Abstract

The most prominent cancer-associated fibroblasts (CAFs) in tumor stroma is known to form a protective structure to support tumor growth. Anterior gradient-2 (AGR2), a tumor secretory protein is believed to play a pivotal role during tumor microenvironment (TME) development. Here, we report that extracellular AGR2 enhances fibroblasts elongation and migration significantly. The early stimulation of RhoA showed the association of AGR2 by upregulation of G1-S phase-regulatory protein cyclin D1 and FAK phosphorylation through fibroblasts growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR). Our finding indicates that secretory AGR2 alters fibroblasts elongation, migration, and organization suggesting the secretory AGR2 as a potential molecular target that might be responsible to alter fibroblasts infiltration to support tumor growth.

Pay attention to membrane tension: Mechanobiology of the cell surface

“… Cell type Speed [μm/min] Tether force [pN] Methods (tether force) How fast does membrane tension propagate? Neurons 0.05–0.7 [ 50 , 51 ] 7-32 [ 52 , 53 , 54 ] OT >10 min [ 22 ] HeLa 0.06 [ 55 ] 13 [ 56 ] OT >10 min [ 22 ] NIH3T3 0.08 [ 57 , 58 ] 7-40 [ 59 , 60 , 61 , 62 ] OT >10 min [ 22 ] MEFs 0.2 [ 56 ] 10 [ 63 ] OT COS-1 0.28–0.5 [ 64 ] 25 [ 64 , 65 ] AFS MDCK 0.55 [ 65 ] 50 [ 66 ] AFS >10 min [ 22 ] Macrophages/BMDM 1–2.5 [ 67 , 68 ] 30-70 [ 18 , 53 ] OT Microglia 1.1 [ 69 ] 60 [ 53 ] OT A2780 1.2 [ 5 ] ...…”

AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment

“…Reports indicate that eAGR2 can infiltrate cells to influence tumor development and invasion from within, leading to the accumulation of β-linker proteins that modulate fibroblasts surrounding tumor cells within the TME [70,72]. AGR2 secreted by ovarian cancer not only sustains tumor growth by regulating the protein cycle and modulating fibroblasts but also acts as a chaperone protein binding to extracellular signaling molecules [75], enhancing its own activity and promoting angiogenesis and tumor growth, including factors like vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) [76]. Furthermore, augmenting signal transduction pathways, eAGR2 ultimately facilitates tumor cell aggregation, migration, and angiogenesis, fostering conditions for tumor growth [76].…”

Construction and stable gene expression of AGR2xPD1 bi-specific antibody that enhances attachment between T-Cells and lung tumor cells, suppress tumor cell migration and promoting CD8 expression in cytotoxic T-cells

“…AGR2 usually resides within ER for its proteostasis and protein folding functions; it also localizes in other cellular compartments, plasma membrane, cytoplasm, and extracellular environment ( Fessart et al, 2021 , Moidu et al, 2020 ). We have reported the role of extracellular AGR2 as paracrine signaling in tumor microenvironment (TME) development ( Mangukiya et al, 2019 , Merugu et al, 2021 ). AGR2 overexpression leads to enhanced cancer cell proliferation, metastasis, and survival, promoting tumor progression and drug resistance ( Li et al, 2015 , Pohler et al, 2004 ).…”