bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–09–12
seven papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer.
  2. Spheroid-on-chip microfluidic technology for the evaluation of the impact of continuous flow on metastatic potential in cancer models in vitro.
  3. Development of Cell-Derived Matrices for Three-Dimensional In Vitro Cancer Cell Models.
  4. Facile Fabrication of Hollow Hydrogel Microfiber via 3D Printing-Assisted Microfluidics and Its Application as a Biomimetic Blood Capillary.
  5. Proteogenomic analysis of pancreatic cancer subtypes.
  6. Pancreatic Lineage Specifier PDX1 Increases Adhesion and Decreases Motility of Cancer Cells.
  7. PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models.
  1. Cancers (Basel). 2021 Sep 06. pii: 4487. [Epub ahead of print]13(17):
    Organ-Chip Models: Opportunities for Precision Medicine in Pancreatic Cancer.
    Muhammad R Haque, Trevor H Rempert, Taslim A Al-Hilal, Chengyao Wang, Abhinav Bhushan, Faraz Bishehsari.
      Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6-8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of "organ-on-a-chip" approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.
    Keywords:  microfluidics; organ-on-a-chip; pancreatic ductal adenocarcinoma; tissue engineering; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13174487
  2. Biomicrofluidics. 2021 Jul;15(4): 044103
    Spheroid-on-chip microfluidic technology for the evaluation of the impact of continuous flow on metastatic potential in cancer models in vitro.
    Thomas Collins, Emily Pyne, Martin Christensen, Alexander Iles, Nicole Pamme, Isabel M Pires.
      The majority of cancer deaths are linked to tumor spread, or metastasis, but 3D in vitro metastasis models relevant to the tumor microenvironment (including interstitial fluid flow) remain an area of unmet need. Microfluidics allows us to introduce controlled flow to an in vitro cancer model to better understand the relationship between flow and metastasis. Here, we report new hybrid spheroid-on-chip in vitro models for the impact of interstitial fluid flow on cancer spread. We designed a series of reusable glass microfluidic devices to contain one spheroid in a microwell under continuous perfusion culture. Spheroids derived from established cancer cell lines were perfused with complete media at a flow rate relevant to tumor interstitial fluid flow. Spheroid viability and migratory/invasive capabilities were maintained on-chip when compared to off-chip static conditions. Importantly, using flow conditions modeled in vitro, we are the first to report flow-induced secretion of pro-metastatic factors, in this case cytokines vascular endothelial growth factor and interleukin 6. In summary, we have developed a new, streamlined spheroid-on-chip in vitro model that represents a feasible in vitro alternative to conventional murine in vivo metastasis assays, including complex tumor environmental factors, such as interstitial fluid flow, extracellular matrices, and using 3D models to model nutrient and oxygen gradients. Our device, therefore, constitutes a robust alternative to in vivo early-metastasis models for determination of novel metastasis biomarkers as well as evaluation of therapeutically relevant molecular targets not possible in in vivo murine models.
    DOI:  https://doi.org/10.1063/5.0061373
  3. ACS Appl Mater Interfaces. 2021 Sep 08.
    Development of Cell-Derived Matrices for Three-Dimensional In Vitro Cancer Cell Models.
    Gerard Rubí-Sans, Agata Nyga, Elena Rebollo, Soledad Pérez-Amodio, Jorge Otero, Daniel Navajas, Miguel A Mateos-Timoneda, Elisabeth Engel.
      Most morphogenetic and pathological processes are driven by cells responding to the surrounding matrix, such as its composition, architecture, and mechanical properties. Despite increasing evidence for the role of extracellular matrix (ECM) in tissue and disease development, many in vitro substitutes still fail to effectively mimic the native microenvironment. We established a novel method to produce macroscale (>1 cm) mesenchymal cell-derived matrices (CDMs) aimed to mimic the fibrotic tumor microenvironment surrounding epithelial cancer cells. CDMs are produced by human adipose mesenchymal stem cells cultured in sacrificial 3D scaffold templates of fibronectin-coated poly-lactic acid microcarriers (MCs) in the presence of macromolecular crowders. We showed that decellularized CDMs closely mimic the fibrillar protein composition, architecture, and mechanical properties of human fibrotic ECM from cancer masses. CDMs had highly reproducible composition made of collagen types I and III and fibronectin ECM with tunable mechanical properties. Moreover, decellularized and MC-free CDMs were successfully repopulated with cancer cells throughout their 3D structure, and following chemotherapeutic treatment, cancer cells showed greater doxorubicin resistance compared to 3D culture in collagen hydrogels. Collectively, these results support the use of CDMs as a reproducible and tunable tool for developing 3D in vitro cancer models.
    Keywords:  3D cell-derived matrices; adipose mesenchymal stem cells; cytotoxicity assay; extracellular microenvironment; macromolecular crowders; microcarriers
    DOI:  https://doi.org/10.1021/acsami.1c13630
  4. ACS Biomater Sci Eng. 2021 Sep 10.
    Facile Fabrication of Hollow Hydrogel Microfiber via 3D Printing-Assisted Microfluidics and Its Application as a Biomimetic Blood Capillary.
    Dongxu Lan, Yulian Shang, Hongxian Su, Minhua Liang, Yang Liu, Haofei Li, Qi Feng, Xiaodong Cao, Hua Dong.
      Simulating the structure and function of blood capillaries is very important for an in-depth insight into their role in the human body and treatment of capillary-related diseases. Due to the similar composition and structure, hollow hydrogel microfibers are well-recognized as potential biomimetic blood capillaries. In this paper, we report a novel, facile, and reproducible method to fabricate coaxial microfluidic chips via 3D printing-assisted soft lithography and then hollow hydrogel microfibers using the as-prepared coaxial microfluidic chips. Instead of traditional photoresist-based lithography, 3D printing of gelatin hydrogel under various extrusion pressures is used to construct sacrificial templates of coaxial microfluidic chips. Various solid and hollow hydrogel microfibers with complicated and hierarchical structures can be obtained via multitype coaxial microfluidic chips or a combination of coaxial microfluidic fabrication and post-treatment. The as-formed hollow hydrogel microfibers are evaluated in detail as biomimetic blood capillaries, including physicochemical and cytological properties. Our results prove that the hollow hydrogel microfibers exhibit excellent mass transport capacity, hemocompatibility, semipermeability, and mechanical strength, and their barrier function can be further enhanced in the presence of endothelial cells. Overall, our 3D printing-assisted fabrication strategy provides a new technique to construct microfluidic chips with complicated 3D microchannels, and the resulting hollow hydrogel microfibers are promising candidates for blood capillaries.
    Keywords:  3D printing; barrier function; biomimetic blood capillary; coaxial microfluidic chip; hollow hydrogel microfiber
    DOI:  https://doi.org/10.1021/acsbiomaterials.1c00980
  5. PLoS One. 2021 ;16(9): e0257084
    Proteogenomic analysis of pancreatic cancer subtypes.
    Doris Kafita, Panji Nkhoma, Mildred Zulu, Musalula Sinkala.
      Pancreatic cancer remains a significant public health problem with an ever-rising incidence of disease. Cancers of the pancreas are characterised by various molecular aberrations, including changes in the proteomics and genomics landscape of the tumour cells. Therefore, there is a need to identify the proteomic landscape of pancreatic cancer and the specific genomic and molecular alterations associated with disease subtypes. Here, we carry out an integrative bioinformatics analysis of The Cancer Genome Atlas dataset, including proteomics and whole-exome sequencing data collected from pancreatic cancer patients. We apply unsupervised clustering on the proteomics dataset to reveal the two distinct subtypes of pancreatic cancer. Using functional and pathway analysis based on the proteomics data, we demonstrate the different molecular processes and signalling aberrations of the pancreatic cancer subtypes. In addition, we explore the clinical characteristics of these subtypes to show differences in disease outcome. Using datasets of mutations and copy number alterations, we show that various signalling pathways previously associated with pancreatic cancer are altered among both subtypes of pancreatic tumours, including the Wnt pathway, Notch pathway and PI3K-mTOR pathways. Altogether, we reveal the proteogenomic landscape of pancreatic cancer subtypes and the altered molecular processes that can be leveraged to devise more effective treatments.
    DOI:  https://doi.org/10.1371/journal.pone.0257084
  6. Cancers (Basel). 2021 Aug 30. pii: 4390. [Epub ahead of print]13(17):
    Pancreatic Lineage Specifier PDX1 Increases Adhesion and Decreases Motility of Cancer Cells.
    Liya Kondratyeva, Igor Chernov, Eugene Kopantzev, Dmitry Didych, Alexey Kuzmich, Irina Alekseenko, Sergey Kostrov, Eugene Sverdlov.
      Intercellular interactions involving adhesion factors are key operators in cancer progression. In particular, these factors are responsible for facilitating cell migration and metastasis. Strengthening of adhesion between tumor cells and surrounding cells or extracellular matrix (ECM), may provide a way to inhibit tumor cell migration. Recently, we demonstrated that PDX1 ectopic expression results in the reduction of pancreatic cancer line PANC-1 cell motility in vitro and in vivo, and we now provide experimental data confirming the hypothesis that suppression of migration may be related to the effect of PDX1 on cell adhesion. Cell migration analyses demonstrated decreased motility of pancreatic Colo357 and PANC-1 cell lines expressing PDX1. We observed decreased expression levels of genes associated with promoting cell migration and increased expression of genes negatively affecting cell motility. Expression of the EMT regulator genes was only mildly induced in cells expressing PDX1 during the simulation of the epithelial-mesenchymal transition (EMT) by the addition of TGFβ1 to the medium. PDX1-expressing cancer cell lines showed increased cell adhesion to collagen type I, fibronectin, and poly-lysine. We conclude that ectopic expression of PDX1 reduces the migration potential of cancer cells, by increasing the adhesive properties of cells and reducing the sensitivity to TGFβ1-induced EMT.
    Keywords:  PDX1; cancer metastasis; cell adhesion; cell migration; epithelial-mesenchymal transition; pancreatic cancer
    DOI:  https://doi.org/10.3390/cancers13174390
  7. J Exp Clin Cancer Res. 2021 Sep 10. 40(1): 286
    PEGylated recombinant human hyaluronidase (PEGPH20) pre-treatment improves intra-tumour distribution and efficacy of paclitaxel in preclinical models.
    Lavinia Morosi, Marina Meroni, Paolo Ubezio, Ilaria Fuso Nerini, Lucia Minoli, Luca Porcu, Nicolò Panini, Marika Colombo, Barbara Blouw, David W Kang, Enrico Davoli, Massimo Zucchetti, Maurizio D'Incalci, Roberta Frapolli.
       BACKGROUND: Scarce drug penetration in solid tumours is one of the possible causes of the limited efficacy of chemotherapy and is related to the altered tumour microenvironment. The abnormal tumour extracellular matrix (ECM) together with abnormal blood and lymphatic vessels, reactive stroma and inflammation all affect the uptake, distribution and efficacy of anticancer drugs.
    METHODS: We investigated the effect of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) pre-treatment in degrading hyaluronan (hyaluronic acid; HA), one of the main components of the ECM, to improve the delivery of antitumor drugs and increase their therapeutic efficacy. The antitumor activity of paclitaxel (PTX) in HA synthase 3-overexpressing and wild-type SKOV3 ovarian cancer model and in the BxPC3 pancreas xenograft tumour model, was evaluated by monitoring tumour growth with or without PEGPH20 pre-treatment. Pharmacokinetics and tumour penetration of PTX were assessed by HPLC and mass spectrometry imaging analysis in the same tumour models. Tumour tissue architecture and HA deposition were analysed by histochemistry.
    RESULTS: Pre-treatment with PEGPH20 modified tumour tissue architecture and improved the antitumor activity of paclitaxel in the SKOV3/HAS3 tumour model, favouring its accumulation and more homogeneous intra-tumour distribution, as assessed by quantitative and qualitative analysis. PEGPH20 also reduced HA content influencing, though less markedly, PTX distribution and antitumor activity in the BxPC3 tumour model.
    CONCLUSION: Remodelling the stroma of HA-rich tumours by depletion of HA with PEGPH20 pre-treatment, is a potentially successful strategy to improve the intra-tumour distribution of anticancer drugs, increasing their therapeutic efficacy, without increasing toxicity.
    Keywords:  Drug distribution; Extracellular matrix; Hyaluronan; Mass spectrometry imaging; Solid tumours
    DOI:  https://doi.org/10.1186/s13046-021-02070-x
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