Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network

Abstract

Background Excessive extracellular matrix deposition and increased stiffness are typical features of solid tumors such as hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). These conditions create confined spaces for tumor cell migration and metastasis. The regulatory mechanism of confined migration remains unclear. Methods LC–MS was applied to determine the differentially expressed proteins between HCC tissues and corresponding adjacent tissue. Collective migration and single cell migration microfluidic devices with 6 μm-high confined channels were designed and fabricated to mimic the in vivo confined space. 3D invasion assay was created by Matrigel and Collagen I mixture treat to adherent cells. 3D spheroid formation under various stiffness environment was developed by different substitution percentage GelMA. Immunoprecipitation was performed to pull down the LH1-binding proteins, which were identified by LC–MS. Immunofluorescent staining, FRET, RT-PCR, Western blotting, FRAP, CCK-8, transwell cell migration, wound healing, orthotopic liver injection mouse model and in vivo imaging were used to evaluate the target expression and cellular phenotype. Results Lysyl hydroxylase 1 (LH1) promoted the confined migration of cancer cells at both collective and single cell levels. In addition, LH1 enhanced cell invasion in a 3D biomimetic model and spheroid formation in stiffer environments. High LH1 expression correlated with poor prognosis of both HCC and PDAC patients, while it also promoted in vivo metastasis. Mechanistically, LH1 bound and stabilized Septin2 (SEPT2) to enhance actin polymerization, depending on the hydroxylase domain. Finally, the subpopulation with high expression of both LH1 and SEPT2 had the poorest prognosis. Conclusions LH1 promotes the confined migration and metastasis of cancer cells by stabilizing SEPT2 and thus facilitating actin polymerization.

Polydopamine-Based Resveratrol-Hyaluronidase Nanomedicine Inhibited Pancreatic Cancer Cell Invasive Phenotype in Hyaluronic Acid Enrichment Tumor Sphere Model

“…Some cells seem like octopuses, and all filopodia are in a deviated direction. But in a 2D environment, cells seem to move randomly, without a specific target in a regular culture environment . Besides this, in this work, we provided an objective method to measure the invasion ability of tumor spheres under limited conditions, even a photo under an optical microscope can only show a slide cut between 2D and 3D situations.…”

“…But in a 2D environment, cells seem to move randomly, without a specific target in a regular culture environment. 24 Besides this, in this work, we provided an objective method to measure the invasion ability of tumor spheres under limited conditions, even a photo under an optical microscope can only show a slide cut between 2D and 3D situations. Considering anoikis 25 could be induced in noattached cells, we bring in the GelMA hydrogel system to be an attachable center of the tumor sphere.…”

The versatile roles of testrapanins in cancer from intracellular signaling to cell–cell communication: cell membrane proteins without ligands

“…There are also some discrepancies in the function of specific TSPAN members in cancer cell proliferation and invasion. TSPAN31 and TSPAN7 can promote migration of hepatocellular carcinoma and myeloma cells respectively, but do not affect cell proliferation [ 30 , 66 ]. More interestingly, TSPAN12 could inhibit the growth of breast cancer cells, but facilitate metastasis [ 44 ].…”

“…Metastasis is the leading cause of cancer-related deaths and the failure of cancer treatment [ 28 ]. The development of metastases requires cancer cells to leave their primary site (local invasion), intravasate, circulate and survival in the bloodstream, extravasate, acclimate in a secondary site, and finally form new colonization foci [ 29 , 30 ]. Indeed, all cellular behaviors, including cancer cell migration, invasion, proliferation, apoptosis, should be concisely coordinated to ensure cancer metastasis [ 31 , 32 ].…”

Unveiling the potential of HKUST-1: synthesis, activation, advantages and biomedical applications

“…These unique properties of copper are pivotal in their anti-tumor, antibacterial, and wound-healing effects, highlighting their potential in various therapeutic applications. 11,12 In 1999, Chui et al pioneered the synthesis of the threedimensional structure of HKUST-1, also known as MOF-199 or Cu 3 (BTC) 2 , using a solvothermal method. 13 HKUST-1 primarily consists of copper salts and an acidic ligand, often cupric nitrate trihydrate (Cu(NO 3 ) 2 Á3H 2 O) and benzene-1,3,5-tricarboxylic acid (H 3 BTC), making it one of the representative Cu-MOFs.…”