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Clinical & Experimental Metastasis Aug 2022Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely...
Plexin-domain containing 2 (PLXDC2) has been reported as an oncoprotein in several human malignancies. However, its expression and roles in gastric cancer remain largely unclear. In this study, we found that PLXDC2 was highly expressed in gastric cancer tissues, and the expression levels were positively correlated with clinicopathological features, but negatively with the patients' outcome. Cox regression analysis identified PLXDC2 as an independent prognostic indicator for the patients. Knockdown of PLXDC2 markedly suppressed the in vitro invasion and in vivo metastasis of gastric cancer cells, while overexpression of PLXDC2 resulted in opposite effects. Mechanistically, PLXDC2 enhanced the level of phosphorylated Cortactin (p-Cortactin) by physically interacting with protein tyrosine phosphatase 1B (PTP1B), an important dephosphorylase, to prevent its dephosphorylating of p-Cortactin, thereby promoting the formation of invadopodia. Collectively, our results indicate that PLXDC2 contributes to the invasion and metastasis of gastric cancer by inhibiting PTP1B to facilitate the invadopodium formation, and may serve as a potential prognostic biomarker and a therapeutic target for this disease.
Topics: Cell Line, Tumor; Cortactin; Humans; Neoplasm Invasiveness; Phosphoric Monoester Hydrolases; Podosomes; Receptors, Cell Surface; Stomach Neoplasms
PubMed: 35661947
DOI: 10.1007/s10585-022-10168-5 -
Cancer Science Aug 2022Elevated adenosine generated by CD73 (ecto-5'-nucleotidase; NT5E) could boost immunosuppressive responses and promote immune evasion in the tumor microenvironment....
Elevated adenosine generated by CD73 (ecto-5'-nucleotidase; NT5E) could boost immunosuppressive responses and promote immune evasion in the tumor microenvironment. However, despite the immune response, CD73 could also promote tumor progression in a variety of cancers, and the nonimmunologic role and corresponding molecular mechanism of CD73 involved in head and neck squamous cell carcinoma (HNSCC) progression are not well characterized. Here, we demonstrated that CD73/NT5E is overexpressed in HNSCC tissues and predicts poor prognosis. Suppression of CD73 inhibited the proliferation, migration, and invasion of HNSCC cell lines (CAL27 and HN4) in vitro and in vivo. Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) predicted that CD73 may be involved in invadopodia formation and MAPK signaling activation. As expected, knockdown of CD73 inhibited the MAPK signaling pathway, and the suppressive effect of CD73 knockdown on proliferation, migration, invasion, and invadopodia formation was reversed by a MAPK signaling activator. Our results suggest that CD73 could promote the proliferation, migration, invasion, and invadopodia formation of HNSCC via the MAPK signaling pathway and provide new mechanistic insights into the nonimmunological role of CD73 in HNSCC.
Topics: 5'-Nucleotidase; Cell Line, Tumor; Cell Movement; Cell Proliferation; GPI-Linked Proteins; Head and Neck Neoplasms; Humans; Podosomes; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment
PubMed: 35657703
DOI: 10.1111/cas.15452 -
The Journal of Biological Chemistry Jul 2022Invadopodia on cancer cells play crucial roles in tumor invasion and metastasis by degrading and remodeling the surrounding extracellular matrices and driving cell...
Invadopodia on cancer cells play crucial roles in tumor invasion and metastasis by degrading and remodeling the surrounding extracellular matrices and driving cell migration in complex 3D environments. Previous studies have indicated that microtubules (MTs) play a crucial role in elongation of invadopodia, but not their formation, probably by regulating delivery of membrane and secretory proteins within invadopodia. However, the identity of the responsible MT-based molecular motors and their regulation has been elusive. Here, we show that KIF1C, a member of kinesin-3 family, is localized to the tips of invadopodia and is required for their elongation and the invasion of cancer cells. We also found that c-Src phosphorylates tyrosine residues within the stalk domain of KIF1C, thereby enhancing its association with tyrosine phosphatase PTPD1, that in turn activates MT-binding ability of KIF1C, probably by relieving the autoinhibitory interaction between its motor and stalk domains. These findings shed new insights into how c-Src signaling is coupled to the MT-dependent dynamic nature of invadopodia and also advance our understanding of the mechanism of KIF1C activation through release of its autoinhibition.
Topics: Cell Line, Tumor; Genes, src; Humans; Kinesins; Microtubules; Neoplasm Invasiveness; Phosphorylation; Podosomes; Protein Tyrosine Phosphatases, Non-Receptor; Tyrosine
PubMed: 35654143
DOI: 10.1016/j.jbc.2022.102090 -
Journal of Cell Science May 2022Podosomes are mechanosensitive protrusive actin structures that are prominent in myeloid cells, and they have been linked to vascular extravasation. Recent studies have...
Podosomes are mechanosensitive protrusive actin structures that are prominent in myeloid cells, and they have been linked to vascular extravasation. Recent studies have suggested that podosomes are hierarchically organized and have coordinated dynamics on the cell scale, which implies that the local force generation by single podosomes can be different from their global combined action. Complementary to previous studies focusing on individual podosomes, here we investigated the cell-wide force generation of podosome-bearing ER-Hoxb8 monocytes. We found that the occurrence of focal tractions accompanied by a cell-wide substrate indentation cannot be explained by summing the forces of single podosomes. Instead, our findings suggest that superimposed contraction on the cell scale gives rise to a buckling mechanism that can explain the measured cell-scale indentation. Specifically, the actomyosin network contraction causes peripheral in-plane substrate tractions, while the accumulated internal stress results in out-of-plane deformation in the central cell region via a buckling instability, producing the cell-scale indentation. Hence, we propose that contraction of the actomyosin network, which connects the podosomes, leads to a substrate indentation that acts in addition to the protrusion forces of individual podosomes. This article has an associated First Person interview with the first author of the paper.
Topics: Actomyosin; Cell Surface Extensions; Humans; Monocytes; Podosomes; Traction
PubMed: 35621127
DOI: 10.1242/jcs.259042 -
Calcified Tissue International Aug 2022Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint...
Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat peri-prosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mice skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1, and the downstream target gene Hes1 in Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for the treatment of peri-prosthetic osteolysis and other osteolytic disease associated with overactive osteoclasts.
Topics: Alanine; Animals; Azepines; Bone Resorption; Disease Models, Animal; Mice; Mice, Inbred C57BL; NF-kappa B; Osteoclasts; Osteogenesis; Osteolysis; RANK Ligand; Signal Transduction; Solubility; Titanium
PubMed: 35588014
DOI: 10.1007/s00223-022-00980-2 -
Oncogene Jun 2022Non-small cell lung cancer (NSCLC) is one of leading causes of cancer-related mortality worldwide, which harbors various accumulated genetic and epigenetic...
Non-small cell lung cancer (NSCLC) is one of leading causes of cancer-related mortality worldwide, which harbors various accumulated genetic and epigenetic abnormalities. Histone methyltransferase SETDB1 is a pivotal epigenetic regulator whose focal amplification and upregulation are commonly detected in NSCLC. However, molecular mechanisms underlying the pro-oncogenic function of SETDB1 remain poorly characterized. Here, we demonstrate that SETDB1 augments the migration and invasion capabilities of NSCLC cells by reinforcing invadopodia formation and mediated ECM degradation. At the molecular level, SETDB1 suppresses the expression of FOXA2, a crucial tumor and metastasis suppressor via coordinated epigenetic mechanisms - SETDB1 not only catalyzes histone H3K9 methylation on FOXA2 genomic locus, but also recruits DNMT3A to regulate DNA methylation on CpG island. Consequently, depletion of Setdb1 in murine lung adenocarcinoma cells completely abolished their full and spontaneous metastatic capabilities in mouse xenograft models. These findings together establish the pro-metastasis activity of SETDB1 in NSCLC and elucidate the underlying cellular and molecular mechanisms.
Topics: Adenocarcinoma of Lung; Animals; Carcinoma, Non-Small-Cell Lung; DNA Methylation; Histone-Lysine N-Methyltransferase; Histones; Humans; Lung Neoplasms; Mice; Neoplasm Metastasis; Podosomes
PubMed: 35546351
DOI: 10.1038/s41388-022-02345-3 -
Journal of Clinical Medicine Apr 2022Metastasis accounts for the majority of cancer-related deaths. Despite decades of research, the prevention and suppression of metastasis remain an elusive goal, and to...
Metastasis accounts for the majority of cancer-related deaths. Despite decades of research, the prevention and suppression of metastasis remain an elusive goal, and to date, only a few metastasis-related genes have been targeted therapeutically. Thus, there is a strong need to find potential genes involved in key driver traits of metastasis and their available drugs. In this study, we identified genes associated with metastasis and repurposable drugs that potentially target them. First, we use text mining of PubMed citations to identify candidate genes associated with metastatic processes, such as invadopodia, motility, movement, metastasis, invasion, wound healing, EMT (epithelial to mesenchymal transition), and podosome. Next, we annotated the top genes involved in each process as a driver, tumor suppressor, or oncogene. Then, a total of 185 unique cancer genes involved in metastasis-related processes were used for hub gene analysis using bioinformatics tools. Notably, a total of 77 hub genes were identified. Further, we used virtual screening data of druggable candidate hub genes involved in metastasis and identified potential drugs that can be repurposed as anti-metastatic drugs. Remarkably, we found a total of 50 approved drugs that have the potential to be repurposed against 19 hub genes involved in metastasis-related processes. These 50 drugs were also found to be validated in different cancer cell lines, such as , , , and targeting SRC, MMP2, PTK2B, and RAC1 hub genes, respectively. These repurposed drugs potentially target metastasis, provide pharmacodynamic insight, and offer a window of opportunity for the development of much-needed antimetastatic drugs.
PubMed: 35456223
DOI: 10.3390/jcm11082130 -
Scientific Reports Apr 2022Bone marrow megakaryocytes (MKs) undergo a maturation involving contacts with the microenvironment before extending proplatelets through sinusoids to deliver platelets...
Bone marrow megakaryocytes (MKs) undergo a maturation involving contacts with the microenvironment before extending proplatelets through sinusoids to deliver platelets in the bloodstream. We demonstrated that MKs assemble linear F-actin-enriched podosomes on collagen I fibers. Microscopy analysis evidenced an inverse correlation between the number of dot-like versus linear podosomes over time. Confocal videomicroscopy confirmed that they derived from each-other. This dynamics was dependent on myosin IIA. Importantly, MKs progenitors expressed the Tks4/5 adaptors, displayed a strong gelatinolytic ability and did not form linear podosomes. While maturing, MKs lost Tks expression together with digestive ability. However, those MKs were still able to remodel the matrix by exerting traction on collagen I fibers through a collaboration between GPVI, ß1 integrin and linear podosomes. Our data demonstrated that a change in structure and composition of podosomes accounted for the shift of function during megakaryopoiesis. These data highlight the fact that members of the invadosome family could correspond to different maturation status of the same entity, to adapt to functional responses required by differentiation stages of the cell that bears them.
Topics: Blood Platelets; Collagen Type I; Megakaryocytes; Podosomes; Thrombopoiesis
PubMed: 35428815
DOI: 10.1038/s41598-022-10215-x -
Science Advances Apr 2022Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, where they switch from a contractile to a synthetic phenotype. Because of...
Vascular smooth muscle cells (VSMCs) play a central role in the progression of atherosclerosis, where they switch from a contractile to a synthetic phenotype. Because of their role as risk factors for atherosclerosis, we sought here to systematically study the impact of matrix stiffness and (hemodynamic) pressure on VSMCs. Thereby, we find that pressure and stiffness individually affect the VSMC phenotype. However, only the combination of hypertensive pressure and matrix compliance, and as such mechanical stimuli that are prevalent during atherosclerosis, leads to a full phenotypic switch including the formation of matrix-degrading podosomes. We further analyze the molecular mechanism in stiffness and pressure sensing and identify a regulation through different but overlapping pathways culminating in the regulation of the actin cytoskeleton through cofilin. Together, our data show how different pathological mechanical signals combined but through distinct pathways accelerate a phenotypic switch that will ultimately contribute to atherosclerotic disease progression.
Topics: Atherosclerosis; Cell Proliferation; Cells, Cultured; Humans; Muscle, Smooth, Vascular; Phenotype
PubMed: 35427166
DOI: 10.1126/sciadv.abm3471 -
BMC Cancer Apr 2022Invadopodia, actin-rich structures that release metallo-proteases at the interface with extra-cellular matrix, in a punctate manner are thought to be important drivers...
BACKGROUND
Invadopodia, actin-rich structures that release metallo-proteases at the interface with extra-cellular matrix, in a punctate manner are thought to be important drivers of tumour invasion. Invadopodia formation has been observed in-vitro and in-vivo in numerous metastatic cell lines derived from multiple tumour types. However, prostate cancer cell lines have not been routinely reported to generate invadopodia and the few instances have always required external stimulation.
METHODS
In this study, the invasive potential of primary prostate adenocarcinoma cell lines, which have never been fully characterised before, was investigated both in-vitro invadopodia assays and in-vivo zebrafish dissemination assay. Subsequently, circulating tumour cells from prostate cancer patients were isolated and tested in the invadopodia assay.
RESULTS
Retention of E-cadherin and N-cadherin expression indicated a transitional state of EMT progression, consistent with the idea of partial EMT that has been frequently observed in aggressive prostate cancer. All cell lines tested were capable of spontaneous invadopodia formation and possess a significant degradative ability in-vitro under basal conditions. These cell lines were invasive in-vivo and produced visible metastasis in the zebrafish dissemination assay. Importantly we have proceeded to demonstrate that circulating tumour cells isolated from prostate cancer patients exhibit invadopodia-like structures and degrade matrix with visible puncta. This work supports a role for invadopodia activity as one of the mechanisms of dissemination employed by prostate cancer cells.
CONCLUSION
The combination of studies presented here provide clear evidence that invadopodia activity can play a role in prostate cancer progression.
Topics: Animals; Cell Line, Tumor; Extracellular Matrix; Humans; Male; Neoplasm Invasiveness; Neoplastic Cells, Circulating; Podosomes; Prostate; Prostatic Neoplasms; Zebrafish
PubMed: 35397545
DOI: 10.1186/s12885-022-09424-4