Quantifying cancer epithelial-mesenchymal plasticity and its association with stemness and immune response

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial-mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor. Moreover, cancer cells in hybrid E/M phenotypes tend to be more associated with stemness which endows them with tumor-initiation ability and therapy resistance. Most recently, cells undergoing EMT have been shown to promote immune suppression for better survival. A systematic understanding of the emergence of hybrid E/M phenotypes and the connection of EMT with stemness and immune suppression would contribute to more effective therapeutic strategies. In this review, we first discuss recent efforts combining theoretical and experimental approaches to elucidate mechanisms underlying EMT multi-stability (i.e. the existence of multiple stable phenotypes during EMT) and the properties of hybrid E/M phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell cooperation and extracellular matrix. Afterwards, we discuss various metrics that can be used to quantify EMT spectrum. We further describe possible mechanisms underlying the formation of clusters of circulating tumor cells. Last but not least, we summarize recent systems biology analysis of the role of EMT in the acquisition of stemness and immune suppression.Comment: 50 pages, 6 figure

Acoustic transmission enhancement through a periodically-structured stiff plate without any opening

We report both experimentally and theoretically that the enhanced acoustic transmission can occur in the subwavelength region through a thin but stiff structured-plate without any opening. This exotic acoustic phenomenon is essentially distinct from the previous related studies originated from, either collectively or individually, the interaction of the incident wave with openings in previous structures. It is attributed to the structure-induced resonant excitation of the non-leaky Lamb modes that exist intrinsically in the uniform elastic plate. Our finding should have impact on ultrasonic applications.Comment: 11 pages, 4 figure

Mass Ratio Distribution of Hierarchical Triple Systems from the LAMOST-MRS Survey

Hierarchical triple-star systems consists of three components organised into an inner binary ($M_{1}$,$M_{2}$) and a more distant outer tertiary ($M_{3}$) star. The LAMOST Medium-Resolution Spectroscopic Survey (LAMOST-MRS) has offered a great sample for the study of triple system populations. We used the Peak Amplitude Ratio (PAR) method to obtain the mass ratio ($q_\mathrm{{in}}$, $q_\mathrm{{out}}$) of a triple system from its normalised spectrum. By calculating Cross-Correlation Function (CCF), we determined the correlation between the mass ratio $q_\mathrm{{out}}$ ($M_{3}$/($M_{1}$+$M_{2}$)) and the amplitude ratio ($A_{3}$/($A_{1}$+$A_{2}$)). We derived $q_\mathrm{{in}}$ of $0.5-1.0$ and $q_\mathrm{{out}}$ between 0.2 and 0.8. By fitting a power-law function of the corrected $q_\mathrm{{in}}$ distribution, the $\gamma_\mathrm{{in}}$ are estimated to be $-0.654\pm2.915$, $4.304\pm1.125$ and $11.371\pm1.309$ for A, F and G type stars. The derived $\gamma_\mathrm{{in}}$-values increase as the mass decrease, indicating that less massive stars are more likely to have companion stars with similar masses. By fitting a power-law function of the corrected $q_\mathrm{{out}}$ distribution, the ${\gamma_\mathrm{{out}}}$ are estimated to be $-2.016\pm0.172$, $-1.962\pm0.853$ and $-1.238\pm0.141$ for G, F and A type stars, respectively. The ${\gamma_\mathrm{{out}}}$-values show a trend of growth toward lower primary star masses

Observation of orbital order in the van der Waals material 1T−TiSe2

Besides magnetic and charge order, regular arrangements of orbital occupation constitute a fundamental order parameter of condensed matter physics. Even though orbital order is difficult to identify directly in experiments, its presence was firmly established in a number of strongly correlated, three-dimensional Mott insulators. Here, reporting resonant x-ray-scattering experiments on the layered van der Waals compound 1T-TiSe2, we establish that the known charge density wave in this weakly correlated, quasi-two-dimensional material corresponds to an orbital ordered phase. Our experimental scattering results are consistent with first-principles calculations that bring to the fore a generic mechanism of close interplay between charge redistribution, lattice displacements, and orbital order. It demonstrates the essential role that orbital degrees of freedom play in TiSe2, and their importance throughout the family of correlated van der Waals materials

Enhancement of Canonical Wnt/β-Catenin Signaling Activity by HCV Core Protein Promotes Cell Growth of Hepatocellular Carcinoma Cells

BACKGROUND: The Hepatitis C virus (HCV) core protein has been implicated as a potential oncogene or a cofactor in HCV-related hepatocellular carcinoma (HCC), but the underlying mechanisms are unknown. Overactivation of the Wnt/β-catenin signaling is a major factor in oncogenesis of HCC. However, the pathogenesis of HCV core-associated Wnt/β-catenin activation remains to be further characterized. Therefore, we attempted to determine whether HCV core protein plays an important role in regulating Wnt/β-catenin signaling in HCC cells. METHODOLOGY: Wnt/β-catenin signaling activity was investigated in core-expressing hepatoma cells. Protein and gene expression were examined by Western blot, immunofluorescence staining, RT-qPCR, and reporter assay. PRINCIPAL FINDINGS: HCV core protein significantly enhances Tcf-dependent transcriptional activity induced by Wnt3A in HCC cell lines. Additionally, core protein increases and stabilizes β-catenin levels in hepatoma cell line Huh7 through inactivation of GSK-3β, which contributes to the up-regulation of downstream target genes, such as c-Myc, cyclin D1, WISP2 and CTGF. Also, core protein increases cell proliferation rate and promotes Wnt3A-induced tumor growth in the xenograft tumor model of human HCC. CONCLUSIONS/SIGNIFICANCE: HCV core protein enhances Wnt/β-catenin signaling activity, hence playing an important role in HCV-associated carcinogenesis

Accumulation of MDSC subsets in renal cell carcinoma correlates with grade and progression free survival, and is associated with intratumoral expression of IL-1β, IL-8 and CXCL5

Myeloid derived suppressor cells (MDSC, CD33+CD11b+ HLA-DR low/-) play a major role in tumor-mediated immune evasion and are composed of at least 3 subsets PMN (CD15+), monocytic (CD14+) and lineage-negative (CD15-CD14-), and each has been shown to be significantly increased in some human tumor types and to correlate with metastatic burden, clinical cancer stage and outcome. Less in known about the MDSC subsets that accumulate in tumors such as renal cell carcinoma (RCC) and the cytokines/chemokines involved in their recruitment. Flow cytometry analysis of peripheral blood mononuclear cells (PBMC, n = 20) and nephrectomy samples (n = 39, stage 1-4) showed increased levels of total MDSC in RCC patients compared to normal controls (n = 15), with PMN- and Lin- MDSC subsets dominating in the blood and tumor of RCC patients. Blood levels of total MDSC, PMN-MDSC and Lin-MDSC correlated with tumor grade (p = 0.026, p = 0.006 and p = 0.045, respectively), while blood levels of total MDSC and Lin-MDSC correlated with progression free survival (PFS) in patients with limited stage disease (n = 16, stages 1-3) (HR = 1.35, p = 0.03; HR = 1.45, p = 0.02, respectively). In the tumor, higher PMN-MDSC levels were significantly associated with decreased PFS (n = 29, HR = 1.09, p = 0.011). To assess the role of select chemokines (IL-8, CXCL5, Mip-1α, MCP-1 and Rantes) and of the pro-inflammatory cytokine IL-1β in promoting the accumulation of MDSC within the tumor, these proteins were quantitated in tumor lysates by ELISA and correlated to MDSC frequencies (Spearman correlations). We found a direct correlation between the frequency of PMN-MDSC in the parenchyma and the levels of IL-8 (p < 0.001), CXCL-5 (p < 0.001), and IL-1β (p = 0.029). Frequency of parenchymal Lin- MDSC directly correlated with levels of IL-8 (p = 0.033) and CXCL-5 (p = 0.008), but not IL-1β. In circulation, frequency of total MDSCs directly correlated with IL-1β plasma levels (p = 0.003).\ud \ud To further define the role of IL-1β in MDSC accumulation within tumors, we overexpressed IL-1β in RENCA and CT26 tumors and compared them to untransfected tumors. Overexpression of IL-1β resulted in enhanced tumor growth and increased frequency of intratumor PMN-MDSC (10.3X in RENCA and 26X in CT26), with a modest increase in intratumor M-MDSC. A large fraction of tumor infiltrating PMN-MDSC expressed CXCR2 (84% in RENCA and 55% in CT26), which is associated with a significant increase in expression of CXCR2 ligands (KC, CXCL5, and MIP2). These results support the idea that IL-1β-mediated induction of select chemokines promotes the accumulation of MDSC, particularly PMN-MDSC, within tumors, resulting in enhanced immune suppression and angiogenesis

Activated leukocyte cell adhesion molecule (ALCAM)/CD166 in pancreatic cancer, a pivotal link to clinical outcome and vascular embolism.

Activated leukocyte cell adhesion molecule (ALCAM, or CD166) is a cell adhesion molecule and one of potential tumour metastasis 'soil' receptors that via homotypic and heterotypic interactions, mediates cancer cell adhesion. The present study investigated clinical, pathological and prognostic values of ALCAM in patients with pancreatic cancer. Human pancreatic cancer (PANC-1 and Mia PaCa-2) and human vascular endothelial cell lines were used to construct cell models differentially expressing levels of ALCAM. Tumour-endothelial interaction and tumour migration were assessed by a DiI-based method and electric cell-substrate impedance sensing (ECIS) assay. Pancreatic cancer tissues (n=223), collected immediately after surgery, were analysed for levels of the ALCAM transcripts, which were also analysed against clinical, pathological and clinical outcomes of the patients. ALCAM protein was assessed by immunohistochemistry on a tissue array. Our study demonstrate that pancreatic cancer tissues had significantly higher levels of ALCAM transcripts than normal tissues (P<0.00001). There were no significant differences with staging, differentiation and tumour locations. Tumours from patients who died of pancreatic cancer had significantly high levels of ALCAM compared with those who lived (P=0.018), and this finding was further supported by ROC analysis (P=0.016). Multivariant analysis showed that ALCAM is an independent prognosis factor for overall survival (HR=5.485), with both nodal status and TNM staging contributing to the model (HR=2.578 and 3.02, respectively). A surprising finding was the relationship between ALCAM expression and microvessel embolism of tumour cells (P=0.021, with vs without tumour embolism). Levels of ALCAM were found to be a determinant factor to adherence of the pancreatic cancer cells to vascular endothelial cells, as demonstrated by pancreatic cancer cell models genetically engineered to express differential levels of ALCAM. The tumour-endothelial interaction mediated by ALCAM was readily blocked by addition of soluble ALCAM. Our data supports the conclusion that ALCAM expression is aberrant in pancreatic cancer and its raised expression is an independent prognostic factor for the survival of the patients and the microvascular embolism by cancer cells. Our results suggest that ALCAM plays a key role in mediating tumour-endothelial cell interactions and enhancing tumour embolism in pancreatic cancer, and targeting ALCAM represents a potential therapeutic strategy for treating human pancreatic cancer

Activated leukocyte cell adhesion molecule (ALCAM)/CD166 in pancreatic cancer, a pivotal link to clinical outcome and vascular embolism

Activated leukocyte cell adhesion molecule (ALCAM, or CD166) is a cell adhesion molecule and one of potential tumour metastasis ‘soil’ receptors that via homotypic and heterotypic interactions, mediates cancer cell adhesion. The present study investigated clinical, pathological and prognostic values of ALCAM in patients with pancreatic cancer. Human pancreatic cancer (PANC-1 and Mia PaCa-2) and human vascular endothelial cell lines were used to construct cell models differentially expressing levels of ALCAM. Tumour-endothelial interaction and tumour migration were assessed by a DiI-based method and electric cell-substrate impedance sensing (ECIS) assay. Pancreatic cancer tissues (n=223), collected immediately after surgery, were analysed for levels of the ALCAM transcripts, which were also analysed against clinical, pathological and clinical outcomes of the patients. ALCAM protein was assessed by immunohistochemistry on a tissue array. Our study demonstrate that pancreatic cancer tissues had significantly higher levels of ALCAM transcripts than normal tissues (P<0.00001). There were no significant differences with staging, differentiation and tumour locations. Tumours from patients who died of pancreatic cancer had significantly high levels of ALCAM compared with those who lived (P=0.018), and this finding was further supported by ROC analysis (P=0.016). Multivariant analysis showed that ALCAM is an independent prognosis factor for overall survival (HR=5.485), with both nodal status and TNM staging contributing to the model (HR=2.578 and 3.02, respectively). A surprising finding was the relationship between ALCAM expression and microvessel embolism of tumour cells (P=0.021, with vs without tumour embolism). Levels of ALCAM were found to be a determinant factor to adherence of the pancreatic cancer cells to vascular endothelial cells, as demonstrated by pancreatic cancer cell models genetically engineered to express differential levels of ALCAM. The tumour-endothelial interaction mediated by ALCAM was readily blocked by addition of soluble ALCAM. Our data supports the conclusion that ALCAM expression is aberrant in pancreatic cancer and its raised expression is an independent prognostic factor for the survival of the patients and the microvascular embolism by cancer cells. Our results suggest that ALCAM plays a key role in mediating tumour-endothelial cell interactions and enhancing tumour embolism in pancreatic cancer, and targeting ALCAM represents a potential therapeutic strategy for treating human pancreatic cancer

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead