bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–08–22
eleven papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. PIN1 Inhibition Synergizes with Immunochemotherapy in Pancreatic Cancer.
  2. Shedding Light on the Role of Neurotransmitters in the Microenvironment of Pancreatic Cancer.
  3. Organ-on-chip applications in drug discovery: an end user perspective.
  4. The vascular niche in next generation microphysiological systems.
  5. Microengineered perfusable 3D-bioprinted glioblastoma model for in vivo mimicry of tumor microenvironment.
  6. Generation of hypoxia-sensing chimeric antigen receptor T cells.
  7. Simultaneous 2D and 3D cell culture array for multicellular geometry, drug discovery and tumor microenvironment reconstruction.
  8. TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma.
  9. Nrf2 expression in pancreatic stellate cells promotes progression of cancer.
  10. Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.
  11. PD-L1 correlated gene expression profiles and tumor infiltrating lymphocytes in pancreatic cancer.
  1. Cancer Discov. 2021 Aug 20.
    PIN1 Inhibition Synergizes with Immunochemotherapy in Pancreatic Cancer.
      PIN1 inhibition in combination with immunochemotherapy caused pancreatic tumor regression in vivo.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-118
  2. Front Cell Dev Biol. 2021 ;9 688953
    Shedding Light on the Role of Neurotransmitters in the Microenvironment of Pancreatic Cancer.
    Yiyi Liang, Huimin Li, Yu Gan, Hong Tu.
      Pancreatic cancer (PC) is a highly lethal malignancy with a 5-year survival rate of less than 8%. The fate of PC is determined not only by the malignant behavior of the cancer cells, but also by the surrounding tumor microenvironment (TME), consisting of various cellular (cancer cells, immune cells, stromal cells, endothelial cells, and neurons) and non-cellular (cytokines, neurotransmitters, and extracellular matrix) components. The pancreatic TME has the unique characteristic of exhibiting increased neural density and altered microenvironmental concentration of neurotransmitters. The neurotransmitters, produced by both neuron and non-neuronal cells, can directly regulate the biological behavior of PC cells via binding to their corresponding receptors on tumor cells and activating the intracellular downstream signals. On the other hand, the neurotransmitters can also communicate with other cellular components such as the immune cells in the TME to promote cancer growth. In this review, we will summarize the pleiotropic effects of neurotransmitters on the initiation and progression of PC, and particularly discuss the emerging mechanisms of how neurotransmitters influence the innate and adaptive immune responses in the TME in an autocrine or paracrine manner. A better understanding of the interplay between neurotransmitters and the immune cells in the TME might facilitate the development of new effective therapies for PC.
    Keywords:  immune cells; immunotherapy; neurotransmitter; pancreatic cancer; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fcell.2021.688953
  3. Biochem Soc Trans. 2021 Aug 16. pii: BST20210840. [Epub ahead of print]
    Organ-on-chip applications in drug discovery: an end user perspective.
    Naomi Clapp, Augustin Amour, Wendy C Rowan, Pelin L Candarlioglu.
      Organ-on-chip (OoC) systems are in vitro microfluidic models that mimic the microstructures, functions and physiochemical environments of whole living organs more accurately than two-dimensional models. While still in their infancy, OoCs are expected to bring ground-breaking benefits to a myriad of applications, enabling more human-relevant candidate drug efficacy and toxicity studies, and providing greater insights into mechanisms of human disease. Here, we explore a selection of applications of OoC systems. The future directions and scope of implementing OoCs across the drug discovery process are also discussed.
    Keywords:  drug development; drug discovery; microfluidic models; organ-on-a-chip
    DOI:  https://doi.org/10.1042/BST20210840
  4. Lab Chip. 2021 Aug 16.
    The vascular niche in next generation microphysiological systems.
    Makena L Ewald, Yu-Hsi Chen, Abraham P Lee, Christopher C W Hughes.
      In recent years, microphysiological system (MPS, also known as, organ-on-a-chip or tissue chip) platforms have emerged with great promise to improve the predictive capacity of preclinical modeling thereby reducing the high attrition rates when drugs move into trials. While their designs can vary quite significantly, in general MPS are bioengineered in vitro microenvironments that recapitulate key functional units of human organs, and that have broad applications in human physiology, pathophysiology, and clinical pharmacology. A critical next step in the evolution of MPS devices is the widespread incorporation of functional vasculature within tissues. The vasculature itself is a major organ that carries nutrients, immune cells, signaling molecules and therapeutics to all other organs. It also plays critical roles in inducing and maintaining tissue identity through expression of angiocrine factors, and in providing tissue-specific milieus (i.e., the vascular niche) that can support the survival and function of stem cells. Thus, organs are patterned, maintained and supported by the vasculature, which in turn receives signals that drive tissue specific gene expression. In this review, we will discuss published vascularized MPS platforms and present considerations for next-generation devices looking to incorporate this critical constituent. Finally, we will highlight the organ-patterning processes governed by the vasculature, and how the incorporation of a vascular niche within MPS platforms will establish a unique opportunity to study stem cell development.
    DOI:  https://doi.org/10.1039/d1lc00530h
  5. Sci Adv. 2021 Aug;pii: eabi9119. [Epub ahead of print]7(34):
    Microengineered perfusable 3D-bioprinted glioblastoma model for in vivo mimicry of tumor microenvironment.
    Lena Neufeld, Eilam Yeini, Noa Reisman, Yael Shtilerman, Dikla Ben-Shushan, Sabina Pozzi, Asaf Madi, Galia Tiram, Anat Eldar-Boock, Shiran Ferber, Rachel Grossman, Zvi Ram, Ronit Satchi-Fainaro.
      Many drugs show promising results in laboratory research but eventually fail clinical trials. We hypothesize that one main reason for this translational gap is that current cancer models are inadequate. Most models lack the tumor-stroma interactions, which are essential for proper representation of cancer complexed biology. Therefore, we recapitulated the tumor heterogenic microenvironment by creating fibrin glioblastoma bioink consisting of patient-derived glioblastoma cells, astrocytes, and microglia. In addition, perfusable blood vessels were created using a sacrificial bioink coated with brain pericytes and endothelial cells. We observed similar growth curves, drug response, and genetic signature of glioblastoma cells grown in our 3D-bioink platform and in orthotopic cancer mouse models as opposed to 2D culture on rigid plastic plates. Our 3D-bioprinted model could be the basis for potentially replacing cell cultures and animal models as a powerful platform for rapid, reproducible, and robust target discovery; personalized therapy screening; and drug development.
    DOI:  https://doi.org/10.1126/sciadv.abi9119
  6. STAR Protoc. 2021 Sep 17. 2(3): 100723
    Generation of hypoxia-sensing chimeric antigen receptor T cells.
    Paris Kosti, Karen I Larios-Martinez, John Maher, James N Arnold.
      Exploiting hypoxia in solid malignancies to restrict expression of chimeric antigen receptors (CARs) on engineered T cells to the tumor microenvironment overcomes the risk of on-target off-tumor toxicity and minimizes tonic signaling, which promotes CAR T cell exhaustion. This protocol summarizes the synthetic biology underlying the development of a stringent oxygen-sensitive CAR for in vitro and in vivo preclinical characterization. For complete details on the use and execution of this protocol, please refer to Kosti et al. (2021).
    Keywords:  Biotechnology and bioengineering; Cancer; Cell culture; Cell isolation; Cell separation/fractionation; Cell-based assays; Flow cytometry/mass cytometry; Immunology; Molecular biology
    DOI:  https://doi.org/10.1016/j.xpro.2021.100723
  7. Biofabrication. 2021 Aug 18.
    Simultaneous 2D and 3D cell culture array for multicellular geometry, drug discovery and tumor microenvironment reconstruction.
    Shun Li, Kaifu Yang, Xiangyan Chen, Xinglong Zhu, Hanying Zhou, Ping Li, Yu Chen, Ying Jiang, Tingting Li, Xiang Qin, Hong Yang, Chunhui Wu, Ji Bao, Fengming You, Yiyao Liu.
      Cell culture systems are indispensable in vitro tools for biomedical research. Although conventional two-dimensional (2D) cell cultures are still used for most biomedical and biological studies, the three dimensional (3D) cell culture technology attracts increasing attention from researchers, especially in cancer and stem cell research. Due to the different spatial structures, cells in 2D and 3D cultures exhibit different biochemical and biophysical phenotypes. Therefore, a new platform with both 2D and 3D cell cultures is needed to bridge the gap between 2D and 3D cell-based assays. Here, a simultaneous 2D and 3D cell culture array system was constructed by microprinting technology, in which cancer cells exhibited heterozygous geometry structures with both 2D monolayers and 3D spheroids. Cells grown in 3D spheroids showed higher proliferation ability and stronger cell-cell adhesion. Spheroids derived from various types of cancer cell lines exhibited distinct morphologies through a geometrical confinement stimulated biomechanical transduction. Z-projected images of cancer cell aggregates were used to analyze 3D multicellular architecture features. Notably, by using a support vector machine (SVM) classifier, we distinguished tumor cells from normal cells with an accuracy greater than 95%, according to the geometrical features of multicellular spheroids in phase contrast microscopy images. Cancer cells in multicellular spheroid arrays exhibited higher drug resistance of anticancer drug cisplatin than cells grown in 2D cultures. Finally, we developed a co-culture system composed of tumor spheroid arrays, fibroblast cells and photo-crosslinkable gelatin methacryloyl (GelMA) hydrogel to mimic tumor microenvironment which consisted of solid tumor massed, surrounding stromal cells and extracellular matrix. Together, our newly developed simultaneous 2D and 3D cell culture array has great potential in comprehensive evaluation of cellular events in both 2D and 3D, rapid production of spheroid arrays and multicellular geometry-based tumor cell detection (MGTD).
    Keywords:  2D & 3D cell co-culture; cancer cell spheroid; multicellular geometry; tumor cell classification; tumor microenvironment
    DOI:  https://doi.org/10.1088/1758-5090/ac1ea8
  8. Oncogene. 2021 Aug 16.
    TLR2 activation promotes tumour growth and associates with patient survival and chemotherapy response in pancreatic ductal adenocarcinoma.
    Joanne Lundy, Linden J Gearing, Hugh Gao, Alison C West, Louise McLeod, Virginie Deswaerte, Liang Yu, Sean Porazinski, Marina Pajic, Paul J Hertzog, Daniel Croagh, Brendan J Jenkins.
      Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, and is plagued by a paucity of targeted treatment options and tumour resistance to chemotherapeutics. The causal link between chronic inflammation and PDAC suggests that molecular regulators of the immune system promote disease pathogenesis and/or therapeutic resistance, yet their identity is unclear. Here, we couple endoscopic ultrasound-guided fine-needle aspiration, which captures tumour biopsies from all stages, with whole transcriptome profiling of PDAC patient primary tumours to reveal enrichment of the innate immune Toll-like receptor 2 (TLR2) molecular pathway. Augmented TLR2 expression associated with a 4-gene "TLR2 activation" signature, and was prognostic for survival and predictive for gemcitabine-based chemoresistance. Furthermore, antibody-mediated anti-TLR2 therapy suppressed the growth of human PDAC tumour xenografts, independent of a functional immune system. Our results support TLR2-based therapeutic targeting for precision medicine in PDAC, with further clinical utility that TLR2 activation is prognostic and predictive for chemoresponsiveness.
    DOI:  https://doi.org/10.1038/s41388-021-01992-2
  9. Am J Physiol Gastrointest Liver Physiol. 2021 08 18.
    Nrf2 expression in pancreatic stellate cells promotes progression of cancer.
    Yu Tanaka, Shin Hamada, Ryotaro Matsumoto, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune.
      It was previously identified that systemic Nrf2-deletion attenuates pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in a-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs from Nrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium of Nrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells co-injected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those co-injected with Nrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.
    Keywords:  Nrf2; oxidative stress; pancreatic fibrosis; pancreatic stellate cell; stroma
    DOI:  https://doi.org/10.1152/ajpgi.00120.2021
  10. Cancer Cell. 2021 Aug 18. pii: S1535-6108(21)00402-5. [Epub ahead of print]
    Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.
    Yujue Wang, Sixue Liu, Zhentao Yang, Alain P Algazi, Shirley H Lomeli, Yan Wang, Megan Othus, Aayoung Hong, Xiaoyan Wang, Chris E Randolph, Alexis M Jones, Marcus W Bosenberg, Stephanie D Byrum, Alan J Tackett, Henry Lopez, Clayton Yates, David B Solit, Antoni Ribas, Marco Piva, Gatien Moriceau, Roger S Lo.
      Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
    Keywords:  BRAF/NRAS/KRAS/NF1; MAPK/BRAF/MEK inhibitor resistance; anti-CTLA-4; anti-PD-1/L1; brain metastasis; colorectal carcinoma; melanoma; pancreatic ductal adenocarcinoma; sequential-combination therapy; tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2021.07.023
  11. Int J Med Sci. 2021 ;18(14): 3150-3157
    PD-L1 correlated gene expression profiles and tumor infiltrating lymphocytes in pancreatic cancer.
    Jiajin Li, Lu Yin, Yumei Chen, Shuxian An, Yi Xiong, Gang Huang, Jianjun Liu.
      Objective: To study the expression and clinical value of PD-L1 gene in pancreatic cancer, and to predict the role of PD-L1 gene in the development of pancreatic cancer. Methods: The pancreatic cancer datasets were downloaded from the Cancer Genome Atlas (TCGA) and the Oncomine to obtain the PD-L1 gene expression profile and clinical information. Bioinformatics methods were used to analyze the correlation between the expression level of PD-L1 gene in pancreatic cancer and clinicopathological indicators, as well as its influence on prognosis. GSEA and WGCNA analysis was performed to predict the possible pathways of PD-L1 gene regulation in pancreatic cancer. TIMER and MCP-counter were used for PD-L1 with immune infiltration. The genes interact with PD-L1 were also investigated by STING and immunoco-precipitation combined with mass spectrometry analysis (IP-MS). Results: In TCGA database, the overall survival of patients with high expression of PD-L1 gene was significantly lower than that of patients with low expression of PD-L1 gene (χ2 = 12.52, P < 0.001). The samples with high expression of PD-L1 gene showed enrichment of 8 pathways including toll-like receptor signaling pathway and NOD receptor signaling pathway (P < 0.01, FDR < 0.05). Immune infiltration analysis suggested that PD-L1 were associated with monocytic lineage (r = 0.5). The proteins interacting with PD-L1 are mainly concentrated in RNA binding, ribosome, spliceosome and other biological processes or pathways. Conclusion: PD-L1 gene may play an important role in the development of pancreatic cancer and is expected to be a prognostic indicator of pancreatic cancer.
    Keywords:  GSEA; PD-L1; Pancreatic cancer; Prognostic value; TCGA
    DOI:  https://doi.org/10.7150/ijms.61771
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