Podoplanin drives dedifferentiation and amoeboid invasion of melanoma

Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. Melanoma cells utilise amoeboid migration as mode of local invasion. Amoeboid invasion is characterized by rounded cell morphology and high actomyosin contractility driven by the RhoA signalling pathway. Migrastatic drugs targeting actin polymerization and contractility to inhibit invasion and metastasis are therefore a promising treatment option. To predict amoeboid invasion and metastatic potential, there is a need for biomarkers functionally linked to contractility pathways. The glycoprotein podoplanin drives actomyosin contractility in lymphoid fibroblasts, and is overexpressed in several cancer types. Here, we show that podoplanin enhances amoeboid invasion in melanoma. Expression of podoplanin in murine melanoma models drives rounded cell morphology, increasing motility and invasion in vivo. Podoplanin expression is upregulated in a subset of dedifferentiated human melanoma, and in vitro is sufficient to suppress melanogenesis and upregulate melanoma-associated markers Mitf and Pou3f2. Together, our data indicates that podoplanin is both a potential biomarker for dedifferentiated invasive melanoma and a promising migrastatic therapeutic target.

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Long Non-coding RNA ST8SIA6-AS1 Promotes Lung Adenocarcinoma Progression Through Sponging miR-125a-3p

Frontiers in Genetics ◽

10.3389/fgene.2020.597795 ◽

2020 ◽

Vol 11 ◽

Author(s):

Qifeng Cao ◽

Weiqin Yang ◽

Xili Ji ◽

Wei Wang

Keyword(s):

Lung Adenocarcinoma ◽

Critical Role ◽

Diagnosis And Prognosis ◽

Non Coding Rna ◽

Cancer Types ◽

Promising Treatment ◽

Plasma Depletion ◽

Long Non Coding Rna

Emerging evidence suggests that long non-coding RNA (lncRNA) plays a critical role in human disease progression. Recently, a novel lncRNA ST8SIA6-AS1 was shown as an important driver in various cancer types. Nevertheless, its contribution to lung adenocarcinoma (LUAD) remains undocumented. Herein, we found that ST8SIA6-AS1 was frequently overexpressed in LUAD cell lines, tissues, and plasma. Depletion of ST8SIA6-AS1 significantly inhibited LUAD cell proliferation and invasion in vitro and tumor growth in vivo. In term of mechanism, ST8SIA6-AS1 was transcriptionally repressed by tumor suppressor p53, and ST8SIA6-AS1 was mainly located in the cytoplasm and could abundantly sponge miR-125a-3p to increase nicotinamide N-methyltransferase (NNMT) expression, thereby facilitating LUAD malignant progression. Clinically, high ST8SIA6-AS1 was positively correlated with larger tumor size, lymph node metastasis, and later TNM stage. Moreover, ST8SIA6-AS1 was identified as an excellent indicator for MM diagnosis and prognosis. Collectively, our data demonstrate that ST8SIA6-AS1 is a carcinogenic lncRNA in LUAD, and targeting the axis of ST8SIA6-AS1/miR-125a-3p/NNMT may be a promising treatment for LUAD patients.

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Metastatic function of METTL18 in breast cancer via actin methylation and Src

10.1101/831701 ◽

2019 ◽

Cited By ~ 1

Author(s):

Han Gyung Kim ◽

Ji Hye Kim ◽

Woo Seok Yang ◽

Jae Gwang Park ◽

Yong Gyu Lee ◽

...

Keyword(s):

Breast Cancer ◽

Actin Polymerization ◽

Metastatic Potential ◽

Migration And Invasion ◽

Intermediate Form ◽

Breast Cancer Patients ◽

Set Domain ◽

Smooth Muscle Contractility

AbstractRecently, a SET domain containing 3 (SETD3) was identified as an actin histidine methyltransferase, functioning to control replication and pathogenesis in multiple mouse models for enterovirus infection as well as the regulation of smooth muscle contractility linked to primary dystocia. Here, in this study, we report another type of actin histidine methyltransferase, METTL18, that regulates the metastatic potential of breast cancer in human. Among methyltransferases, METTL18 was highly amplified in human breast cancer. In particular, poor prognosis was associated with high expression of METTL18 in HER2-negative breast cancer patients. This gene product was also found to be a critical component of metastatic responses. Loss of METTL18 expression significantly reduced metastatic responses of breast tumor cells both in vitro and in vivo. Mechanistically, it was observed that METTL18 increased actin polymerization, upregulated complex formation with HSP90AA1 and Src, enhanced the activity of an intermediate form of Src with tyrosine phosphorylation at both Y416 and Y527, and induced cellular metastatic responses, including morphological change, migration, and invasion of MDA-MB-231 cells in vitro and in mice. Methylated actin at His73 served as a critical site for interaction with HSP90AA1 and Src to activate p85/PI3K and STAT3. Our findings suggest that METTL18 plays critical roles in metastatic responses of HER2-negative breast cancer cells via actin polymerization and the generation of an intermediate form of Src.

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SCAR is a primary regulator of Arp2/3-dependent morphological events in Drosophila

The Journal of Cell Biology ◽

10.1083/jcb.200109057 ◽

2002 ◽

Vol 156 (4) ◽

pp. 689-701 ◽

Cited By ~ 166

Author(s):

Jennifer A. Zallen ◽

Yehudit Cohen ◽

Andrew M. Hudson ◽

Lynn Cooley ◽

Eric Wieschaus ◽

...

Keyword(s):

Cell Fate ◽

Cell Morphology ◽

Actin Polymerization ◽

Cell Types ◽

Filamentous Actin ◽

Cell Fate Decisions ◽

Cytoplasmic Organization ◽

Multiple Cell

The Arp2/3 complex and its activators, Scar/WAVE and Wiskott-Aldrich Syndrome protein (WASp), promote actin polymerization in vitro and have been proposed to influence cell shape and motility in vivo. We demonstrate that the Drosophila Scar homologue, SCAR, localizes to actin-rich structures and is required for normal cell morphology in multiple cell types throughout development. In particular, SCAR function is essential for cytoplasmic organization in the blastoderm, axon development in the central nervous system, egg chamber structure during oogenesis, and adult eye morphology. Highly similar developmental requirements are found for subunits of the Arp2/3 complex. In the blastoderm, SCAR and Arp2/3 mutations result in a reduction in the amount of cortical filamentous actin and the disruption of dynamically regulated actin structures. Remarkably, the single Drosophila WASp homologue, Wasp, is largely dispensable for these numerous Arp2/3-dependent functions, whereas SCAR does not contribute to cell fate decisions in which Wasp and Arp2/3 play an essential role. These results identify SCAR as a major component of Arp2/3-dependent cell morphology during Drosophila development and demonstrate that the Arp2/3 complex can govern distinct cell biological events in response to SCAR and Wasp regulation.

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Single-cell morphology encodes metastatic potential

Science Advances ◽

10.1126/sciadv.aaw6938 ◽

2020 ◽

Vol 6 (4) ◽

pp. eaaw6938 ◽

Cited By ~ 14

Author(s):

Pei-Hsun Wu ◽

Daniele M. Gilkes ◽

Jude M. Phillip ◽

Akshay Narkar ◽

Thomas Wen-Tao Cheng ◽

...

Keyword(s):

Breast Cancer ◽

Single Cell ◽

Cell Morphology ◽

Clustering Analysis ◽

Breast Cancer Cells ◽

Metastatic Potential ◽

Disease Outcomes ◽

Multidimensional Information

A central goal of precision medicine is to predict disease outcomes and design treatments based on multidimensional information from afflicted cells and tissues. Cell morphology is an emergent readout of the molecular underpinnings of a cell’s functions and, thus, can be used as a method to define the functional state of an individual cell. We measured 216 features derived from cell and nucleus morphology for more than 30,000 breast cancer cells. We find that single cell–derived clones (SCCs) established from the same parental cells exhibit distinct and heritable morphological traits associated with genomic (ploidy) and transcriptomic phenotypes. Using unsupervised clustering analysis, we find that the morphological classes of SCCs predict distinct tumorigenic and metastatic potentials in vivo using multiple mouse models of breast cancer. These findings lay the groundwork for using quantitative morpho-profiling in vitro as a potentially convenient and economical method for phenotyping function in cancer in vivo.

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Vitamin D as potential therapeutic anticancer agent

Journal of Cancer Science and Therapeutics ◽

10.36879/jcst.19.000106 ◽

2018 ◽

pp. 1-3

Keyword(s):

Vitamin D ◽

Anticancer Activity ◽

Anticancer Agent ◽

Antitumor Agents ◽

Metastatic Potential ◽

Anticancer Properties ◽

Chemotherapy Agents

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

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A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

Cell Death and Disease ◽

10.1038/s41419-021-03939-7 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Ying Liu ◽

Wenjie Liu ◽

Ziqiang Yu ◽

Yan Zhang ◽

Yinghua Li ◽

...

Keyword(s):

Bone Loss ◽

Osteoporosis Treatment ◽

Inhibitory Effect ◽

Specific Gene ◽

Actin Ring ◽

Treatment Target ◽

Significant Inhibitory Effect ◽

Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

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AZP2006, a new promising treatment for Alzheimer’s and related diseases

Scientific Reports ◽

10.1038/s41598-021-94708-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

N. Callizot ◽

C. Estrella ◽

S. Burlet ◽

A. Henriques ◽

C. Brantis ◽

...

Keyword(s):

Therapeutic Application ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Potential Therapeutic Application ◽

Promising Treatment ◽

Central Synapses ◽

First Time ◽

Pgrn Level

AbstractProgranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

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The Immunomodulatory Effects of Honey and Associated Flavonoids in Cancer

Nutrients ◽

10.3390/nu13041269 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1269

Author(s):

Razan J. Masad ◽

Shoja M. Haneefa ◽

Yassir A. Mohamed ◽

Ashraf Al-Sbiei ◽

Ghada Bashir ◽

...

Keyword(s):

Immune Responses ◽

Antioxidant Properties ◽

In Vivo Studies ◽

Immunomodulatory Effects ◽

Bioactive Constituents ◽

Cancer Cell Growth ◽

Cancer Types ◽

Immunomodulatory Properties

Honey has exerted a high impact in the field of alternative medicine over many centuries. In addition to its wound healing, anti-microbial and antioxidant properties, several lines of evidence have highlighted the efficiency of honey and associated bioactive constituents as anti-tumor agents against a range of cancer types. Mechanistically, honey was shown to inhibit cancer cell growth through its pro-apoptotic, anti-proliferative and anti-metastatic effects. However, the potential of honey to regulate anti-tumor immune responses is relatively unexplored. A small number of in vitro and in vivo studies have demonstrated the ability of honey to modulate the immune system by inducing immunostimulatory as well as anti-inflammatory effects. In the present review, we summarize the findings from different studies that aimed to investigate the immunomodulatory properties of honey and its flavonoid components in relation to cancer. While these studies provide promising data, additional research is needed to further elucidate the immunomodulatory properties of honey, and to enable its utilization as an adjuvant therapy in cancer.

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Exosomal S100A4 derived from highly metastatic hepatocellular carcinoma cells promotes metastasis by activating STAT3

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00579-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Haoting Sun ◽

Chaoqun Wang ◽

Beiyuan Hu ◽

Xiaomei Gao ◽

Tiantian Zou ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Progression ◽

Calcium Binding ◽

Tumor Metastasis ◽

Metastatic Potential ◽

Functional Roles ◽

Stat3 Phosphorylation ◽

Hcc Cells

AbstractIntercellular cross-talk plays important roles in cancer progression and metastasis. Yet how these cancer cells interact with each other is still largely unknown. Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators. We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma (HCC). Exosomes were extracted from HCC cells of different metastatic potentials. The metastatic effects of exosomes derived from highly metastatic HCC cells (HMH) were evaluated both in vitro and in vivo. Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines, xenograft tumor samples, and functional analyses. Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells (LMH). S100 calcium-binding protein A4 (S100A4) was identified as a functional factor in exosomes derived from HMH. S100A4rich exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4low exosomes or controls. Moreover, exosomal S100A4 could induce expression of osteopontin (OPN), along with other tumor metastasis/stemness-related genes. Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation. HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis. In conclusion, exosomes from HMH could promote the metastatic potential of LMH, and exosomal S100A4 is a key enhancer for HCC metastasis, activating STAT3 phosphorylation and up-regulating OPN expression. This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.

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Distinct roles of tumor associated mutations in collective cell migration

Scientific Reports ◽

10.1038/s41598-021-89130-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rachel M. Lee ◽

Michele I. Vitolo ◽

Wolfgang Losert ◽

Stuart S. Martin

Keyword(s):

Collective Behavior ◽

Metastatic Potential ◽

Breast Epithelial Cell ◽

Collective Cell Migration ◽

Label Free ◽

Collective Migration ◽

Contrast Imaging ◽

Pten Deletion

AbstractRecent evidence suggests that groups of cells are more likely to form clinically dangerous metastatic tumors, emphasizing the importance of understanding mechanisms underlying collective behavior. The emergent collective behavior of migrating cell sheets in vitro has been shown to be disrupted in tumorigenic cells but the connection between this behavior and in vivo tumorigenicity remains unclear. We use particle image velocimetry to measure a multidimensional migration phenotype for genetically defined human breast epithelial cell lines that range in their in vivo behavior from non-tumorigenic to aggressively metastatic. By using cells with controlled mutations, we show that PTEN deletion enhances collective migration, while Ras activation suppresses it, even when combined with PTEN deletion. These opposing effects on collective migration of two mutations that are frequently found in patient tumors could be exploited in the development of novel treatments for metastatic disease. Our methods are based on label-free phase contrast imaging, and thus could easily be applied to patient tumor cells. The short time scales of our approach do not require potentially selective growth, and thus in combination with label-free imaging would allow multidimensional collective migration phenotypes to be utilized in clinical assessments of metastatic potential.

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