bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–10–03
eight papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. The tumor microenvironment in pancreatic ductal adenocarcinoma: current perspectives and future directions.
  2. Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment.
  3. A novel design of microfluidic platform for metronomic combinatorial chemotherapy drug screening based on 3D tumor spheroid model.
  4. Low-cost rapid prototyping and assembly of an open microfluidic device for a 3D vascularized organ-on-a-chip.
  5. Erlotinib Promotes Ligand-Induced EGFR Degradation in 3D but Not 2D Cultures of Pancreatic Ductal Adenocarcinoma Cells.
  6. Engineering of a functional pancreatic acinus with reprogrammed cancer cells by induced PTF1a expression.
  7. A vascularized tumoroid model for human glioblastoma angiogenesis.
  8. NF-κB and Pancreatic Cancer; Chapter and Verse.
  1. Cancer Metastasis Rev. 2021 Sep 30.
    The tumor microenvironment in pancreatic ductal adenocarcinoma: current perspectives and future directions.
    Cameron J Herting, Isaac Karpovsky, Gregory B Lesinski.
      Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies and is characterized by a unique tumor microenvironment (TME) consisting of an abundant stromal component. Many features contained with the PDAC stroma contribute to resistance to cytotoxic and immunotherapeutic regimens, as well as the propensity for this tumor to metastasize. At the cellular level, PDAC cells crosstalk with a complex mixture of non-neoplastic cell types including fibroblasts, endothelial cells, and immune cells. These intricate interactions fuel the progression and therapeutic resistance of this aggressive cancer. Moreover, data suggest the polarization of these cell types, in particular immune and fibroblast populations, dictate how PDAC tumors grow, metastasize, and respond to therapy. As a result, current research is focused on how to best target these populations to render tumors responsive to treatment. Herein, we summarize the cell populations implicated in providing a supporting role for the development and progression of PDAC. We focus on stromal fibroblasts and immune subsets that have been widely researched. We discuss factors which govern the phenotype of these populations and provide insight on how they have been targeted therapeutically. This review provides an overview of the tumor microenvironment and postulates that cellular and soluble factors within the microenvironment can be specifically targeted to improve patient outcomes.
    Keywords:  Cancer-associated fibroblasts; Pancreatic cancer; Tumor microenvironment immunotherapy
    DOI:  https://doi.org/10.1007/s10555-021-09988-w
  2. Cells. 2021 Aug 26. pii: 2201. [Epub ahead of print]10(9):
    Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment.
    Yuta Ando, Jeong Min Oh, Winfield Zhao, Madeleine Tran, Keyue Shen.
      Solid tumors in advanced cancer often feature a structurally and functionally abnormal vasculature through tumor angiogenesis, which contributes to cancer progression, metastasis, and therapeutic resistances. Hypoxia is considered a major driver of angiogenesis in tumor microenvironments. However, there remains a lack of in vitro models that recapitulate both the vasculature and hypoxia in the same model with physiological resemblance to the tumor microenvironment, while allowing for high-content spatiotemporal analyses for mechanistic studies and therapeutic evaluations. We have previously constructed a hypoxia microdevice that utilizes the metabolism of cancer cells to generate an oxygen gradient in the cancer cell layer as seen in solid tumor sections. Here, we have engineered a new composite microdevice-microfluidics platform that recapitulates a vascularized hypoxic tumor. Endothelial cells were seeded in a collagen channel formed by viscous fingering, to generate a rounded vascular lumen surrounding a hypoxic tumor section composed of cancer cells embedded in a 3-D hydrogel extracellular matrix. We demonstrated that the new device can be used with microscopy-based high-content analyses to track the vascular phenotypes, morphology, and sprouting into the hypoxic tumor section over a 7-day culture, as well as the response to different cancer/stromal cells. We further evaluated the integrity/leakiness of the vascular lumen in molecular delivery, and the potential of the platform to study the movement/trafficking of therapeutic immune cells. Therefore, our new platform can be used as a model for understanding tumor angiogenesis and therapeutic delivery/efficacy in vascularized hypoxic tumors.
    Keywords:  angiogenesis; hypoxia; tumor microenvironment; vasculature; viscous fingering
    DOI:  https://doi.org/10.3390/cells10092201
  3. Biomed Microdevices. 2021 Oct 01. 23(4): 50
    A novel design of microfluidic platform for metronomic combinatorial chemotherapy drug screening based on 3D tumor spheroid model.
    Sharanya Sankar, Viraj Mehta, Subhashini Ravi, Chandra Shekhar Sharma, Subha Narayan Rath.
      For treating cancer at various stages, chemotherapy drugs administered in combination provide better treatment results with lower side effects compared to single-drug therapy. However, finding the potential drug combinations has been challenging due to the large numbers of possible combinations from approved drugs and the failure of in vitro 2D well plate-based cancer models. 3D spheroid-based high-throughput microfluidic platforms recapitulate some of the important features of native tumor tissue and offer a promising alternative to evaluate the combinatory effects of the drugs. This study develops a novel polydimethylsiloxane (PDMS) based microfluidic design with a dynamic environment and strategically placed U-shaped wells for testing all seven possible combinations (three single-drug treatments, three pairwise combinations, treatment with all three drugs) of three chemotherapy drugs (Paclitaxel, Vinorelbine, and Etoposide) on lung tumor spheroids. The design of U-shaped wells has been validated with computational results. Firstly, we test all combinations of drugs on the conventional well plate in static conditions with 3D tumor spheroids. Based on static drug testing results, we show a proof-of-concept by testing the most effective drug combination on the microfluidic device in a dynamic environment. The concentration of the drugs used in combination falls below the maximum tolerated dose (MTD) of the individual drugs, towards low dose metronomic (LDM) chemotherapy. LDM combinatorial chemotherapy identified in this study can potentially lower toxicity and provide better treatment results in cancer patients. The device can be further used to culture patient-specific tumor spheroids and identify synergistic drug combinations for personalized medicine.
    Keywords:  Cancer diagnostics; Combination chemotherapy; Metronomic chemotherapy; Personalized medicine; Tumor spheroids; Tumor-on-a-chip
    DOI:  https://doi.org/10.1007/s10544-021-00593-w
  4. Lab Chip. 2021 Sep 28.
    Low-cost rapid prototyping and assembly of an open microfluidic device for a 3D vascularized organ-on-a-chip.
    Qinyu Li, Kai Niu, Ding Wang, Lian Xuan, Xiaolin Wang.
      Reconstruction of 3D vascularized microtissues within microfabricated devices has rapidly developed in biomedical engineering, which can better mimic the tissue microphysiological function and accurately model human diseases in vitro. However, the traditional PDMS-based microfluidic devices suffer from the microfabrication with complex processes and usage limitations of either material properties or microstructure design, which drive the demand for easy processing and more accessible devices with a user-friendly interface. Here, we present an open microfluidic device through a rapid prototyping method by laser cutting in a cost-effective manner with high flexibility and compatibility. This device allows highly efficient and robust hydrogel patterning under a liquid guiding rail by spontaneous capillary action without the need for surface treatment. Different vascularization mechanisms including vasculogenesis and angiogenesis were performed to construct a 3D perfusable microvasculature inside a tissue chamber with various shapes under different microenvironment factors. Furthermore, as a proof-of-concept we have created a vascularized spheroid by placing a monoculture spheroid into the central through-hole of this device, which formed angiogenesis between the spheroid and microvascular network. This open microfluidic device has great potential for mass customization without the need for complex microfabrication equipment in the cleanroom, which can facilitate studies requiring high-throughput and high-content screening.
    DOI:  https://doi.org/10.1039/d1lc00767j
  5. Cancers (Basel). 2021 Sep 07. pii: 4504. [Epub ahead of print]13(18):
    Erlotinib Promotes Ligand-Induced EGFR Degradation in 3D but Not 2D Cultures of Pancreatic Ductal Adenocarcinoma Cells.
    Nausika Betriu, Anna Andreeva, Carlos E Semino.
      The epithelial growth factor receptor (EGFR) is a tyrosine kinase receptor that participates in many biological processes such as cell proliferation. In addition, EGFR is overexpressed in many epithelial cancers and therefore is a target for cancer therapy. Moreover, EGFR responds to lots of stimuli by internalizing into endosomes from where it can be recycled to the membrane or further sorted into lysosomes where it undergoes degradation. Two-dimensional cell cultures have been classically used to study EGFR trafficking mechanisms in cancer cells. However, it has been widely demonstrated that in 2D cultures cells are exposed to a non-physiological environment as compared to 3D cultures that provide the normal cellular conformation, matrix dimensionality and stiffness, as well as molecular gradients. Therefore, the microenvironment of solid tumors is better recreated in 3D culture models, and this is why they are becoming a more physiological alternative to study cancer physiology. Here, we develop a new model of EGFR internalization and degradation upon erlotinib treatment in pancreatic ductal adenocarcinoma (PDAC) cells cultured in a 3D self-assembling peptide scaffold. In this work, we show that treatment with the tyrosine kinase inhibitor erlotinib promotes EGFR degradation in 3D cultures of PDAC cell lines but not in 2D cultures. We also show that this receptor degradation does not occur in normal fibroblast cells, regardless of culture dimensionality. In conclusion, we demonstrate not only that erlotinib has a distinct effect on tumor and normal cells but also that pancreatic ductal adenocarcinoma cells respond differently to drug treatment when cultured in a 3D microenvironment. This study highlights the importance of culture systems that can more accurately mimic the in vivo tumor physiology.
    Keywords:  3D culture; EGFR; PDAC; degradation; drug resistance; pancreatic ductal adenocarcinoma; self-assembling peptides; trafficking
    DOI:  https://doi.org/10.3390/cancers13184504
  6. Lab Chip. 2021 09 28. 21(19): 3675-3685
    Engineering of a functional pancreatic acinus with reprogrammed cancer cells by induced PTF1a expression.
    Stephanie M Venis, Hye-Ran Moon, Yi Yang, Sagar M Utturkar, Stephen F Konieczny, Bumsoo Han.
      A pancreatic acinus is a functional unit of the exocrine pancreas producing digest enzymes. Its pathobiology is crucial to pancreatic diseases including pancreatitis and pancreatic cancer, which can initiate from pancreatic acini. However, research on pancreatic acini has been significantly hampered due to the difficulty of culturing normal acinar cells in vitro. In this study, an in vitro model of the normal acinus, named pancreatic acinus-on-chip (PAC), is developed using reprogrammed pancreatic cancer cells. The developed model is a microfluidic platform with an epithelial duct and acinar sac geometry microfabricated by a newly developed two-step controlled "viscous-fingering" technique. In this model, human pancreatic cancer cells, Panc-1, reprogrammed to revert to the normal state upon induction of PTF1a gene expression, are cultured. Bioinformatic analyses suggest that, upon induced PTF1a expression, Panc-1 cells transition into a more normal and differentiated acinar phenotype. The microanatomy and exocrine functions of the model are characterized to confirm the normal acinus phenotypes. The developed model provides a new and reliable testbed to study the initiation and progression of pancreatic cancers.
    DOI:  https://doi.org/10.1039/d1lc00350j
  7. Sci Rep. 2021 Oct 01. 11(1): 19550
    A vascularized tumoroid model for human glioblastoma angiogenesis.
    Agavi Stavropoulou Tatla, Alexander W Justin, Colin Watts, Athina E Markaki.
      Glioblastoma (GBM) angiogenesis is critical for tumor growth and recurrence, making it a compelling therapeutic target. Here, a disease-relevant, vascularized tumoroid in vitro model with stem-like features and stromal surrounds is reported. The model is used to recapitulate how individual components of the GBM's complex brain microenvironment such as hypoxia, vasculature-related stromal cells and growth factors support GBM angiogenesis. It is scalable, tractable, cost-effective and can be used with biologically-derived or biomimetic matrices. Patient-derived primary GBM cells are found to closely participate in blood vessel formation in contrast to a GBM cell line containing differentiated cells. Exogenous growth factors amplify this effect under normoxia but not at hypoxia suggesting that a significant amount of growth factors is already being produced under hypoxic conditions. Under hypoxia, primary GBM cells strongly co-localize with umbilical vein endothelial cells to form sprouting vascular networks, which has been reported to occur in vivo. These findings demonstrate that our 3D tumoroid in vitro model exhibits biomimetic attributes that may permit its use as a preclinical model in studying microenvironment cues of tumor angiogenesis.
    DOI:  https://doi.org/10.1038/s41598-021-98911-y
  8. Cancers (Basel). 2021 Sep 07. pii: 4510. [Epub ahead of print]13(18):
    NF-κB and Pancreatic Cancer; Chapter and Verse.
    John Silke, Lorraine Ann O'Reilly.
      Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world's most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials.
    Keywords:  NF-κB; PDAC; Smac mimetics; inflammation; pancreatic cancer; pancreatitis; therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13184510
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