bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–09–05
thirteen papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. Engineered 3D vessel-on-chip using hiPSC-derived endothelial- and vascular smooth muscle cells.
  2. Author Correction: Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells.
  3. Correction: The vascular niche in next generation microphysiological systems.
  4. Tumor microenvironment and metabolic remodeling in gemcitabine-based chemoresistance of pancreatic cancer.
  5. Penetration Cascade of Size Switchable Nanosystem in Desmoplastic Stroma for Improved Pancreatic Cancer Therapy.
  6. Cancer Associated Fibroblasts Derived from Pancreatic Adenocarcinoma and Their Role in Cell Migration.
  7. Putting a PIN in pancreatic cancer.
  8. A histone deacetylase inhibitor, panobinostat, enhances chimeric receptor antigen T cell anti-tumor effect against pancreatic cancer.
  9. Engineering stem cells for cancer immunotherapy.
  10. Organ-on-chip approaches for intestinal 3D in vitro modelling.
  11. Microfluidic Printing of Tunable Hollow Microfibers for Vascular Tissue Engineering.
  12. Organs-on-a-chip models for biological research.
  13. Repositioning of duloxetine to target pancreatic stellate cells.
  1. Stem Cell Reports. 2021 Aug 30. pii: S2213-6711(21)00421-5. [Epub ahead of print]
    Engineered 3D vessel-on-chip using hiPSC-derived endothelial- and vascular smooth muscle cells.
    Marc Vila Cuenca, Amy Cochrane, Francijna E van den Hil, Antoine A F de Vries, Saskia A J Lesnik Oberstein, Christine L Mummery, Valeria V Orlova.
      Crosstalk between endothelial cells (ECs) and pericytes or vascular smooth muscle cells (VSMCs) is essential for the proper functioning of blood vessels. This balance is disrupted in several vascular diseases but there are few experimental models which recapitulate this vascular cell dialogue in humans. Here, we developed a robust multi-cell type 3D vessel-on-chip (VoC) model based entirely on human induced pluripotent stem cells (hiPSCs). Within a fibrin hydrogel microenvironment, the hiPSC-derived vascular cells self-organized to form stable microvascular networks reproducibly, in which the vessels were lumenized and functional, responding as expected to vasoactive stimulation. Vascular organization and intracellular Ca2+ release kinetics in VSMCs could be quantified using automated image analysis based on open-source software CellProfiler and ImageJ on widefield or confocal images, setting the stage for use of the platform to study vascular (patho)physiology and therapy.
    Keywords:  3D vessel-on-chip; VoC; functional readouts; hiPSC-ECs; hiPSC-VSMCs; hiPSC-derived endothelial cells; hiPSC-derived vascular smooth muscle cells; microfluidics; organ-on-chip; vessels-on-chip
    DOI:  https://doi.org/10.1016/j.stemcr.2021.08.003
  2. Sci Rep. 2021 Sep 01. 11(1): 17765
    Author Correction: Impairing flow-mediated endothelial remodeling reduces extravasation of tumor cells.
    Gautier Follain, Naël Osmani, Valentin Gensbittel, Nandini Asokan, Annabel Larnicol, Luc Mercier, Maria Jesus Garcia-Leon, Ignacio Busnelli, Angelique Pichot, Nicodème Paul, Raphaël Carapito, Seiamak Bahram, Olivier Lefebvre, Jacky G Goetz.
      
    DOI:  https://doi.org/10.1038/s41598-021-97172-z
  3. Lab Chip. 2021 Sep 02.
    Correction: The vascular niche in next generation microphysiological systems.
    Makena L Ewald, Yu-Hsi Chen, Abraham P Lee, Christopher C W Hughes.
      Correction for 'The vascular niche in next generation microphysiological systems' by Makena L. Ewald et al., Lab Chip, 2021, DOI: 10.1039/d1lc00530h.
    DOI:  https://doi.org/10.1039/d1lc90093e
  4. Cancer Lett. 2021 Aug 27. pii: S0304-3835(21)00426-2. [Epub ahead of print]521 98-108
    Tumor microenvironment and metabolic remodeling in gemcitabine-based chemoresistance of pancreatic cancer.
    Zongting Gu, Yongxing Du, Xueping Zhao, Chengfeng Wang.
      Pancreatic ductal adenocarcinoma (PDAC) is a solid malignant tumor with a very low operative rate and a poor patient prognosis. Therefore, gemcitabine (GEM)-based chemotherapy remains one of the most important treatment choices for PDAC. However, the efficacy of GEM monotherapy or GEM combination chemotherapy in improving the survival of patients with advanced PDAC is very limited, primarily due to GEM resistance. The mechanism of GEM resistance is complex and unclear. An extensive and dense fibrous matrix in the tumor microenvironment (TME) is an important feature of PDAC. Increasing evidence indicates that this fibrotic TME not only actively participates in the growth and spread of PDAC but also contributes to the induction of GEM resistance. Metabolic remodeling reduces GEM transport and synthesis in PDAC. This review focuses on the main cellular and molecular mechanisms underlying the involvement of the extracellular matrix (ECM), immune cells, and metabolic remodeling in the induction of GEM resistance; highlights the prospect of targeting the TME as an essential strategy to overcome GEM resistance; and provides new precise interventions for chemotherapy sensitization and improving the overall prognosis of patients with PDAC.
    Keywords:  Chemoresistance; Gemcitabine; Metabolic remodeling; Pancreatic ductal adenocarcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2021.08.029
  5. ACS Nano. 2021 Sep 03.
    Penetration Cascade of Size Switchable Nanosystem in Desmoplastic Stroma for Improved Pancreatic Cancer Therapy.
    Xiaozheng Zhao, Xiao Yang, Xudong Wang, Xiao Zhao, Yinlong Zhang, Shaoli Liu, Gregory J Anderson, Seong-Jin Kim, Yiye Li, Guangjun Nie.
      Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-β1 (TGF-β1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.
    Keywords:  TGF-β1 inhibitor; combination therapy; drug penetration; pancreatic cancer; size switchable nanosystem
    DOI:  https://doi.org/10.1021/acsnano.0c08860
  6. Anticancer Res. 2021 Sep;41(9): 4229-4238
    Cancer Associated Fibroblasts Derived from Pancreatic Adenocarcinoma and Their Role in Cell Migration.
    Ellen VON Hoerschelmann, Christopher C M Neumann, Matthaus Felsenstein, Julia Gogolok, Anja Reutzel-Selke, Igor M Sauer, Johann Pratschke, Marcus Bahra, Rosa B Schmuck.
       BACKGROUND/AIM: Pancreatic ductal adenocarcinoma (PDAC) shows poor survival and early systemic dissemination. Cancer associated fibroblasts (CAFs) enhance migration and invasion of cancer cells. We aimed to investigate the role of CAFs in cell migration and their underlying paracrine effects.
    MATERIALS AND METHODS: Using Transwell® migration assays, PDAC cells (PANC-1) and three distinct types of fibroblasts were analyzed: CAFs, genetically transformed human foreskin-fibroblasts (BJeLR), and non-transformed human foreskin-fibroblasts (VH7). IL6 in the culture supernatant was measured to investigate paracrine communication in monocultures and direct/indirect cocultures.
    RESULTS: CAFs showed a significantly higher capacity to migrate in vitro when compared to benign fibroblasts (p=0.009). They also facilitated the migration of PDAC cells in coculture (p=0.001). Neither BJeLR, nor VH7 displayed such features. This was accompanied by a significant increase in IL-6 when CAFs were cocultured with PANC-1 (p=0.009).
    CONCLUSION: CAFs are a key element of intra-tumoral migration and should be further investigated as a potential therapeutic target.
    Keywords:  Pancreatic cancer; cancer associated fibroblasts; migration; paracrine communication.
    DOI:  https://doi.org/10.21873/anticanres.15227
  7. Nat Rev Drug Discov. 2021 Sep 03.
    Putting a PIN in pancreatic cancer.
    M Teresa Villanueva.
      
    DOI:  https://doi.org/10.1038/d41573-021-00153-0
  8. Clin Cancer Res. 2021 Sep 02. pii: clincanres.1141.2021. [Epub ahead of print]
    A histone deacetylase inhibitor, panobinostat, enhances chimeric receptor antigen T cell anti-tumor effect against pancreatic cancer.
    Aesha I Ali, Minyu Wang, Bianca von Scheidt, Pilar M Dominguez, Aaron J Harrison, Daniela G M Tantalo, Jian Kang, Amanda J Oliver, Jack D Chan, Xin Du, Yuchen Bai, Belinda Lee, Ricky W Johnstone, Phillip K Darcy, Michael H Kershaw, Clare Y Slaney.
       PURPOSE: Here we describe a combination chimeric antigen receptor (CAR) T cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model.
    EXPERIMENTAL DESIGN: We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano).
    RESULTS: The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T cell gene accessibility and promoted CAR T cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice.
    CONCLUSIONS: We propose that pancreatic cancer patients could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-1141
  9. Trends Cancer. 2021 Aug 31. pii: S2405-8033(21)00171-0. [Epub ahead of print]
    Engineering stem cells for cancer immunotherapy.
    Yan-Ruide Li, Yang Zhou, Adam Kramer, Lili Yang.
      Engineering stem cells presents an attractive paradigm for cancer immunotherapy. Stem cells engineered to stably express various chimeric antigen receptors (CARs) or T-cell receptors (TCRs) against tumor-associated antigens are showing increasing promise in the treatment of solid tumors and hematologic malignancies. Stem cells engraft for long-term immune cell generation and serve as a sustained source of tumor-specific effector cells to maintain remissions. Furthermore, engineering stem cells provides 'off-the-shelf' cellular products, obviating the need for a personalized and patient-specific product that plagues current autologous cell therapies. Herein, we summarize recent progress of stem cell-engineered cancer therapies, and discuss the utility, impact, opportunities, and challenges of cellular engineering that may facilitate the translational and clinical research.
    Keywords:  T lymphocytes; cancer immunotherapy; chimeric antigen receptor; genetic engineering; natural killer cells; stem cells
    DOI:  https://doi.org/10.1016/j.trecan.2021.08.004
  10. Cell Mol Gastroenterol Hepatol. 2021 Aug 25. pii: S2352-345X(21)00182-X. [Epub ahead of print]
    Organ-on-chip approaches for intestinal 3D in vitro modelling.
    Joana Pimenta, Ricardo Ribeiro, Raquel Almeida, Pedro F Costa, Marta A da Silva, Bruno Pereira.
      The intestinal epithelium has one of the highest turnover rates in the human body, which is supported by intestinal stem cells. Culture models of intestinal physiology have been evolving to incorporate different tissue and microenvironmental elements. However, these models also display gaps that limit their similarity with native conditions. Microfluidics technology arose from the application of microfabrication techniques to fluid manipulation. Recently, microfluidic approaches have been coupled with cell culture, creating self-contained and modular in vitro models with easily controllable features named organs-on-chip. Intestine-on-chip models have enabled the recreation of the proliferative and differentiated compartments of the intestinal epithelium, the long-term maintenance of commensals and the intraluminal perfusion of organoids. Plus, studies based on human primary intestinal cells revealed that these systems have a closer transcriptomic profile and functionality to the intestine in vivo, when compared with other in vitro models. The design flexibility inherent to microfluidic technology allows the simultaneous combination of components such as shear stress, peristalsis-like strain, 3D structure, oxygen gradient and co-cultures with other important cell types involved in gut physiology. The versatility and complexity of the intestine-on-chip grants it the potential for applications in disease modelling, host-microbiota studies, stem cell biology, and, ultimately, the translation to the pharmaceutical industry and clinics, as a reliable high-throughput platform for drug testing and personalized medicine, respectively. This review focuses on the physiological importance of several components that have been incorporated into intestine-on-chip models and highlights interesting features developed in other types of in vitro models that might contribute to the refinement of these systems.
    Keywords:  Intestinal stem cells; Intestine-on-chip; Microfabrication; Organoids
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.08.015
  11. Adv Mater Technol. 2021 Aug;pii: 2000683. [Epub ahead of print]6(8):
    Microfluidic Printing of Tunable Hollow Microfibers for Vascular Tissue Engineering.
    Zhuhao Wu, Hongwei Cai, Zheng Ao, Junhua Xu, Samuel Heaps, Feng Guo.
      Bioprinting of vascular tissues holds great potential in tissue engineering and regenerative medicine. However, challenges remain in fabricating biocompatible and versatile scaffolds for the rapid engineering of vascular tissues and vascularized organs. Here, we report novel bioink-enabled microfluidic printing of tunable hollow microfibers for the rapid formation of blood vessels. By compositing biomaterials including sodium alginate, gelatin methacrylate (GelMA), and glycidyl-methacrylate silk fibroin (SilkMA), we prepared a novel composite bioink with excellent printability and biocompatibility. This composite bioink can be printed into hollow microfibers with tunable dimensions using a microfluidic co-axial printing. After seeding human umbilical vein endothelial cells (HUVEC) into the hollow chambers via a microfluidic prefusion device, these cells can adhere to, grow, proliferate, and then cover the internal surface of the printed hollow scaffolds to form vessel-like tissue structures within three days. By combining the unique composite bioink, microfluidic printing of vascular scaffolds, and microfluidic cell seeding and culturing, our strategy can fabricate vascular-like tissue structures with high viability and tunable dimension within three days. The presented method may engineer in vitro vasculatures for the broad applications in basic research and translational medicine including in vitro disease models, tissue microcirculation, and tissue transplantation.
    Keywords:  Bioprinting; Hollow Microfiber; Microfluidics; Tubular tissues; Vascular Tissue Engineering
    DOI:  https://doi.org/10.1002/admt.202000683
  12. Cell. 2021 Sep 02. pii: S0092-8674(21)00947-8. [Epub ahead of print]184(18): 4597-4611
    Organs-on-a-chip models for biological research.
    Gordana Vunjak-Novakovic, Kacey Ronaldson-Bouchard, Milica Radisic.
      We explore the utility of bioengineered human tissues-individually or connected into physiological units-for biological research. While much smaller and simpler than their native counterparts, these tissues are complex enough to approximate distinct tissue phenotypes: molecular, structural, and functional. Unlike organoids, which form spontaneously and recapitulate development, "organs-on-a-chip" are engineered to display some specific functions of whole organs. Looking back, we discuss the key developments of this emerging technology. Thinking forward, we focus on the challenges faced to fully establish, validate, and utilize the fidelity of these models for biological research.
    DOI:  https://doi.org/10.1016/j.cell.2021.08.005
  13. Oncol Lett. 2021 Oct;22(4): 744
    Repositioning of duloxetine to target pancreatic stellate cells.
    Akiko Sagara, Kohei Nakata, Sokichi Matsumoto, Weiyu Guan, Tomohiko Shinkawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Masafumi Nakamura.
      Pancreatic cancer cells (PCCs) are surrounded by an abundant stroma, which is produced by pancreatic stellate cells (PSCs). PSCs promote tumor cell proliferation and invasion. The objective of the current study was to identify compounds that suppress PSC activation. Gene expression profiles of cancer-derived fibroblasts and normal fibroblasts were used, and the pathway analysis suggested altered pathways that were chosen for validation. It was found that the 'neuroactive ligand-receptor interaction' pathway from the Kyoto Encyclopedia of Genes and Genomes pathway analysis was one of the altered pathways. Several compounds related with this pathway were chosen, and changes in PSC activity were investigated using fluorescence staining of lipid droplets, reverse transcription-quantitative PCR, western blotting, and invasion and migration assays. Among these candidates, duloxetine, a serotonin-noradrenaline reuptake inhibitor, was found to suppress PSC activation and disrupt tumor-stromal interaction. Thus, duloxetine may be a potential drug for suppressing PSC activation and pancreatic cancer growth.
    Keywords:  drug repositioning; duloxetine; pancreatic cancer; pancreatic stellate cells; tumor microenvironment
    DOI:  https://doi.org/10.3892/ol.2021.13005
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