Application of microfluidic chips in anticancer drug screening.

With the continuous development of drug screening technology, new screening methodologies and technologies are constantly emerging, driving drug screening into rapid, efficient and high-throughput development. Microfluidics is a rising star in the development of innovative approaches in drug discovery. In this article, we summarize the recent years' progress of microfluidic chip technology in drug screening, including the developmental history, structural design, and applications in different aspects of microfluidic chips on drug screening. Herein, the existing microfluidic chip screening platforms are summarized from four aspects: chip structure design, sample injection and drive system, cell culture technology on a chip, and efficient remote detection technology. Furthermore, this review discusses the application and developmental prospects of using microfluidic chips in drug screening, particularly in screening natural product anticancer drugs based on chemical properties, pharmacological effects, and drug cytotoxicity.

The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer.

Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.

Tumor-associated CD75s- and iso-CD75s-gangliosides are potential targets for adjuvant therapy in pancreatic cancer.

Pancreatic adenocarcinoma confers one of the highest mortality rates in malignant human tumors with very poor prognosis. Because as yet no treatments are available that produce a substantial survival benefit for this fatal neoplasia, new therapeutic concepts are urgently required to support cancer standard treatment. In search of tumor-associated gangliosides with therapeutic background, we probed a random collection of cancerous and adjacent normal postoperative tissue samples from 38 patients for the expression of CD75s- and iso-CD75s-gangliosides. We exhaustively analyzed the expression of CD75s-1-ganglioside (IV(6)Neu5Ac-nLc4Cer) and structurally closely related iso-CD75s-1-ganglioside (IV(3)Neu5Ac-nLc4Cer) by means of immunohistology of cryosections and semiquantitative TLC of tissue lipid extracts combined with mass spectrometry. CD75s-1- and iso-CD75s-1-ganglioside showed an elevated expression in 42% and 66% of the tumors, respectively, indicating a significant association with neoplastic transformation (P = 0.001). Thus, increased expression of CD75s-1- and iso-CD75s-1-gangliosides renders these cell surface molecules promising candidates for oncologic applications. Further statistical analysis revealed a significant enhancement of CD75s-1-ganglioside in the group of less differentiated tumors (grade >2) suggesting this ganglioside as a potential marker for poor differentiation. The CD75s-specific antitumor drug rViscumin, which represents the recombinant counterpart of the ribosome-inactivating lectin viscumin, has successfully passed clinical phase I trials and provides an opportunity for treating pancreatic cancer. Consequently, if an enhanced expression is existent in malignant tissues, we propose the targeting of CD75s-gangliosides with rViscumin as a novel potential strategy in adjuvant treatment of pancreatic malignancies.

Structural templates predict novel protein interactions and targets from pancreas tumour gene expression data.

MOTIVATION: Pancreatic ductal adenocarcinoma (PDAC) eludes early detection and is characterized by its aggressiveness and resistance to current therapies. A number of gene expression screens have been carried out to identify genes differentially expressed in cancerous tissue. To identify molecular markers and suitable targets, these genes have been mapped to protein interactions to gain an understanding at systems level. RESULTS: Here, we take such a network-centric approach to pancreas cancer by re-constructing networks from known interactions and by predicting novel protein interactions from structural templates. The pathways we find to be largely affected are signal transduction, actin cytoskeleton regulation, cell growth and cell communication. Our analysis indicates that the alteration of the calcium pathway plays an important role in pancreas-specific tumorigenesis. Furthermore, our structural prediction method identifies 40 novel interactions including the tissue factor pathway inhibitor 2 (TFPI2) interacting with the transmembrane protease serine 4 (TMPRSS4). Since TMPRSS4 is involved in metastasis formation, we hypothesize that the upregulation of TMPRSS4 and the downregulation of its predicted inhibitor TFPI2 plays an important role in this process. Moreover, we examine the potential role of BVDU (RP101) as an inhibitor of TMPRSS4. BDVU is known to support apoptosis and prevent the acquisition of chemoresistance. Our results suggest that BVDU might bind to the active site of TMPRSS4, thus reducing its assistance in metastasis. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.