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Eight out of 10 breast cancer patients die within 5 years after the primary tumor has spread to the bones. Tumor cells disseminated from the breast roam the vasculature, colonizing perivascular niches around blood capillaries. Slow flows support the niche maintenance by driving the oxygen, nutrients, and signaling factors from the blood into the interstitial tissue, while extracellular matrix, endothelial cells, and mesenchymal stem cells regulate metastatic homing. Here, we show the feasibility of developing a perfused bone perivascular niche-on-a-chip to investigate the progression and drug resistance of breast cancer cells colonizing the bone. The model is a functional human triculture with stable vascular networks within a 3D native bone matrix cultured on a microfluidic chip. Providing the niche-on-a-chip with controlled flow velocities, shear stresses, and oxygen gradients, we established a long-lasting, self-assembled vascular network without supplementation of angiogenic factors. We further show that human bone marrow-derived mesenchymal stem cells, which have undergone phenotypical transition toward perivascular cell lineages, support the formation of capillary-like structures lining the vascular lumen. Finally, breast cancer cells exposed to interstitial flow within the bone perivascular niche-on-a-chip persist in a slow-proliferative state associated with increased drug resistance. We propose that the bone perivascular niche-on-a-chip with interstitial flow promotes the formation of stable vasculature and mediates cancer cell colonization.

Metastatic colonization, whereby a disseminated tumor cell is able to survive and proliferate at a secondary site, involves both tumor cell-intrinsic and -extrinsic factors. To identify tumor cell-extrinsic (microenvironmental) factors that regulate the ability of metastatic tumor cells to effectively colonize a tissue, we performed a genome-wide screen utilizing the experimental metastasis assay on mutant mice. Mutant and wildtype (control) mice were tail vein-dosed with murine metastatic melanoma B16-F10 cells and 10 days later the number of pulmonary metastatic colonies were counted. Of the 1,300 genes/genetic locations (1,344 alleles) assessed in the screen 34 genes were determined to significantly regulate pulmonary metastatic colonization (15 increased and 19 decreased; P < 0.005 and genotype effect <-55 or >+55). While several of these genes have known roles in immune system regulation (Bach2, Cyba, Cybb, Cybc1, Id2, Igh-6, Irf1, Irf7, Ncf1, Ncf2, Ncf4 and Pik3cg) most are involved in a disparate range of biological processes, ranging from ubiquitination (Herc1) to diphthamide synthesis (Dph6) to Rho GTPase-activation (Arhgap30 and Fgd4), with no previous reports of a role in the regulation of metastasis. Thus, we have identified numerous novel regulators of pulmonary metastatic colonization, which may represent potential therapeutic targets.

Background Single organ metastasis to liver typically occurs in uveal melanoma (UM) and colorectal carcinoma (CRC). Colonization in the host organ is a beachhead step of the metastasis process. The governing pathways of the seeding cells are far away clarified. Objective This study aimed at deciphering governing pathways of the seeding cells that required for metastatic colonization and developing novel strategies against metastasis. Design Mass spectrum analysis of Co-IP pellets was applied to identify the kinase and the substrates of BAP1. Findings were further validated using GST-pull down assay and the proximity ligation assay. The function of CDK6/4-BAP1-VHL signaling axis in promoting liver metastasis was investigated by UM and CRC mouse model. Results Mass spectrum analysis of Co-IP pellets with anti-BAP1 revealed that VHL bound with BAP1. Their physical interaction was further confirmed by GST-pull down assay and proximity ligation assay. We mapped the interacting domains between BAP1 and VHL. In vivo ubiquination assay showed that BAP1 deubiquitinated VHL at K48-linked poly-ubiquitin chain and stabilized VHL protein. Further, exosomal CDK6/4 serine/threonine kinases were identified to phosphorylate BAP1 at S369 to inactivate BAP deubiquitinationase, forming CDK6/4-BAP1-VHL signaling axis. Functionally, BAP1 inhibited CSCs, EMT and metastatic colonization to liver in uveal melanoma and colorectal carcinoma via upregulating VHL protein, which was, however, reversed by targeting CDK6/4. Conclusion In conclusion, VHL is a novel substrate of BAP; and BAP1 suppresses CSCs and metastatic colonization to liver via substrate VHL. These findings may shed lights on the mystery substrates of BAP1 and the underlying mechanism of colonization in liver and intervention targets. Highlights VHL protein is a novel substrate of BAP1 deubiquitinase. The interacting domains between BAP1 and VHL are mapped. BAP1 deubiquitinates and stabilizes VHL in K48-linked poly ubiquitin chain. BAP1 deubiquitinationase activity is inhibited by the S369 phosphorylation of BAP1 that is catalyzed by CDK6/4 kinases, forming CDK6/4-BAP1-VHL signaling axis. CDK6/4-containing tumor derived exosomes secreted by EMT cells and CSCs may further increase CSCs and EMT by an autocrine- or paracrine-like mechanism, forming a positive feedback loop. Targeting CDK6/4 is an effective way to release BAP1 tumor suppressive activity. BAP1 functionally inhibits CSCs and metastatic colonization to liver in uveal melanoma and colorectal carcinoma via stabilizing VHL protein. BAP1 and VHL are negatively correlated with liver metastasis in patients with uveal melanoma and colorectal carcinoma.

High mortality rate and poor survival in melanoma are associated with efficient metastatic colonization. The underlying mechanisms remain elusive. Elucidating the role of exosomes in mediating the interactions between cancer cells and the metastatic microenvironment has been focused on cancer cell derived exosomes in modulating the functions of stromal cells. Whether cancer stem cells (CSCs) can modify the metastatic properties of non-CSC cells, and whether exosomal crosstalk plays a role have not been demonstrated prior to this report. In this study, a paired M14 melanoma derivative cell line, i.e., melanoma parental cell (MPC) and its CSC derivative cell line melanoma stem cell (MSC) were employed. We demonstrated that exosomal crosstalk betwen MSCs and non-CSC MPCs is a new mechanism that underlies melanoma metastasis. Low metastatic melanoma cells (MPCs) can acquire the “metastatic power” from highly metastatic melanoma CSCs (MSCs). We illustrated an uncharacterized microRNA, miR-4535 in mediating such exosomal crosstalk. MSCs deliver its exosomal miR-4535 to the targeted MPCs. Upon entering MPCs, miR-4535 augments metastatic colonization of MPCs by inactivating the autophagy pathway. Graphical Abstract

Ovarian cancer, a frequently occurring gynecological malignancy with a poor prognosis and a 5-year survival rate below 45%, often progresses due to metastatic colonization. This review highlights the potential of traditional Chinese medicine (TCM) monomers as anticancer agents that inhibit the metastatic colonization of ovarian cancer cells. TCM monomers exhibit various mechanisms of action, including (1) inhibiting epithelial-to-mesenchymal transformation by modulating cell adhesion molecules; (2) reducing extracellular matrix damage through inhibition of degrading enzymes; (3) affecting cytoskeletal dynamics to alter cell movement; and (4) preventing angiogenesis by downregulating angiogenic factors. Additionally, TCM monomers can reshape the tumor microenvironment, enhance immune responses, and induce oxidative stress, resulting in reduced proliferation and survival of cancer cells. The comprehensive action of TCM monomers makes them promising candidates for individualized, multi-target therapies in drug-resistant cases. This paper reviews the current research on the mechanisms through which TCM monomers combat metastatic colonization, aiming to provide insights for future studies and clinical applications in ovarian cancer treatment, ultimately offering hope to affected patients.

Background The triple-negative subtype of breast cancer is particularly challenging to treat due to its aggressiveness with a high risk of brain metastasis, and the lack of effective targeted therapies. Tubulin beta 2B class IIb (TUBB2B), a β-tubulin isoform regulating axon guidance during embryonic development, was found to be overexpressed in various types of cancers including triple-negative breast cancer (TNBC). However, its functional roles in breast cancer or metastasis remain unclear. Methods To identify TUBB2B as a novel molecular target in TNBC, we performed bioinformatics analysis to assess the association of TUBB2B expression and survival of patients. RNAscope in situ hybridization was used to examine TUBB2B expression in clinical breast tumor samples. The effect of TUBB2B knockdown on TNBC growth and brain metastasis colonization was evaluated by in vitro and in vivo assays. Mass spectrometry (MS) and biochemical experiments were performed to explore the underlying mechanisms. Preclinical efficacy of targeting TUBB2B was determined in xenograft studies using the siRNA-gold nanoparticle (siRNA-AuNP) approach. Results TUBB2B, but not other β-tubulin isoforms, is frequently overexpressed in TNBC primary tumors as well as brain metastases. We also find that upregulation of TUBB2B is associated with poor prognosis in breast cancer patients. Silencing TUBB2B induces tumor cell death and inhibits the outgrowth of brain metastasis. Mechanistically, we identify eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) as a novel interacting partner of TUBB2B, revealing a previously unexplored role of TUBB2B in translational regulation. In line with its neural-related functions, TUBB2B overexpression in TNBC cells activates astrocytes, which in turn upregulate TUBB2B in tumor cells. These findings suggest a feed-forward interaction between TUBB2B in TNBC cells and astrocytes that promotes brain metastatic colonization. Furthermore, we demonstrate the potent inhibition of TNBC xenograft growth as well as brain metastatic colonization using TUBB2B siRNA-AuNP treatment, indicating potential clinical applications of targeting TUBB2B for TNBC. Conclusions TUBB2B is a novel TNBC gene that plays a key role in promoting tumor cell survival and brain metastatic colonization, and can be targeted by siRNA-AuNPs as a treatment strategy.

Background and purpose Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. Its role in cancer metastasis remains unclear. In this study, we aimed to investigate the potential involvement of ferroptosis in gastric cancer (GC) metastasis. Methods GC cells (AGS, MKN45, HGC27) were used to explore the role of ferroptosis in single and clustered cells with extracellular matrix (ECM) detachment in vitro. We overexpressed glutathione peroxidase 4 (GPX4) to inhibit ferroptosis and assessed the changes in cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Then tumor tissues from 54 GC patients with and without lymphatic metastasis were collected for immunohistochemical staining to investigate the expression of ferroptosis and EMT markers. Finally, Kaplan–Meier survival curves were used to investigate the relationship between overall survival and expression of GPX4 in 178 GC patients. Results Detached single cells had lower viability than adherent cells, but cell clustering improved their survival under matrix-detached conditions. Detached single cells exhibited an induction of iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of ACSL4, TFRC and HO-1, increased iron levels, and changes in mitochondrial morphology. Opposite effects were observed in detached clustered cells, including the upregulation of the ferroptosis suppressors GPX4 and SLC7A11. Overexpression of GPX4 inhibited ferroptosis and promoted GC cell proliferation, migration, invasion, and EMT. Immunohistochemical analysis of tumor tissues from GC patients indicated that lymphatic metastasis was associated with higher potential for ferroptosis inhibition and EMT induction. Finally, Kaplan–Meier survival curves demonstrated a significant decrease in overall survival among GC patients with high GPX4 expression. Conclusions Our study provides the first evidence that inhibition of ferroptosis is a crucial mechanism promoting GC metastasis. GPX4 may be a valuable prognostic factor for GC patients. These findings suggest that targeting ferroptosis inhibition may be a promising strategy for GC patients with metastatic potential. Trial registration The ethical approval code of this study in Institutional Review Board of Peking Union Medical College Hospital is No: K1447.

Background Arginase-1 (ARG1), a urea cycle-related enzyme, catalyzes the hydrolysis of arginine to urea and ornithine, which regulates the proliferation, differentiation, and function of various cells. However, it is unclear whether ARG1 controls the progression and malignant alterations of colon cancer. Methods We established metastatic colonization mouse model and ARG1 overexpressing murine colon cancer CT26 cells to investigate whether activation of ARG1 was related to malignancy of colon cancer cells in vivo. Living cell numbers and migration ability of CT26 cells were evaluated in the presence of ARG inhibitor in vitro. Results Inhibition of arginase activity significantly suppressed the proliferation and migration ability of CT26 murine colon cancer cells in vitro. Overexpression of ARG1 in CT26 cells reduced intracellular l -arginine levels, enhanced cell migration, and promoted epithelial-mesenchymal transition. Metastatic colonization of CT26 cells in lung and liver tissues was significantly augmented by ARG1 overexpression in vivo. ARG1 gene expression was higher in the tumor tissues of liver metastasis than those of primary tumor, and arginase inhibition suppressed the migration ability of HCT116 human colon cancer cells. Conclusion Activation of ARG1 is related to the migration ability and metastatic colonization of colon cancer cells, and blockade of this process may be a novel strategy for controlling cancer malignancy.

Metastasis is the leading cause of tumor-related death from lung cancer. However, limited success has been achieved in the treatment of lung cancer metastasis due to the lack of understanding of the mechanisms that underlie the metastatic process. In this study, Lewis lung carcinoma (LLC) cells which expressed green fluorescent protein in the nucleus and red fluorescent protein in the cytoplasm were used to record metastatic process in real-time via a whole-mouse imaging system. Using this system, we show the neddylation inhibitor MLN4924 inhibits multiple steps of the metastatic process, including intravascular survival, extravasation, and formation of metastatic colonies, thus finally suppressing tumor metastasis. Mechanistically, MLN4924 efficiently inhibits the expression of MMP2, MMP9, and vimentin and disrupts the actin cytoskeleton at an early stage to impair invasive potential and subsequently causes a DNA damage response, cell cycle arrest, and apoptosis upon long exposure to MLN4924. Furthermore, MMP2 and MMP9 are overexpressed in patient lung adenocarcinoma, which conferred a worse overall survival. Together, targeting the neddylation pathway via MLN4924 suppresses multiple steps of the metastatic process, highlighting the potential therapeutic value of MLN4924 for the treatment of metastatic lung cancer.

Long non-coding RNAs (lncRNAs) are involved in carcinogenesis and tumor suppression, and are novel biological tumor regulators. However, the functional roles of lncRNAs and their underlying dysregulation mechanisms in breast cancer are not completely understood. The aim of the present study was to investigate the clinical significance and biological functions of lncRNA TMPO antisense RNA 1 (TMPO-AS1) in breast cancer. TMPO-AS1 levels were measured in human cancer tissues and breast cancer cell lines, and the functional roles of TMPO-AS1 in breast cancer cells were investigated by performing in vitro and in vivo assays. Additionally, luciferase reporter assays were conducted to detect the association between microRNA (miR)-140-5p and TMPO-AS1. TMPO-AS1 expression levels were significantly increased in breast cancer tissues and cell lines compared with adjacent non-cancerous tissues and MCF-10A cells, respectively. In vitro and in vivo studies indicated that TMPO-AS1 knockdown significantly suppressed breast cancer cell viability at 48 and 72 h compared with the small interfering (si)RNA negative control group (NC; siNC). TMPO-AS1 knockdown in vitro inhibited MCF-7 and T47D cell migration and invasion compared with the siNC group. TMPO-AS1 knockdown in metastatic breast cancer cells also decreased metastatic colonization in the mouse lung compared with the short hairpin RNA NC group. Mechanistically, TMPO-AS1 promoted cellular viability and migration as a competing endogenous RNA by sponging miR-140-5p. The results suggested that TMPO-AS1 may serve as a potential therapeutic target in patients with breast cancer.