bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2022–02–13
twelve papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. Fungal Mycobiome Drives IL33 Secretion and TH2 Infiltration in PDAC.
  2. Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity.
  3. Multikinase Inhibition Induces Tumor Microenvironment Remodeling in PDAC.
  4. The Few yet Fabp4ulous Pancreatic Stellate Cells Give Rise to Protumoral CAFs.
  5. The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression.
  6. Blocking breast cancer metastasis.
  7. Vasculature-on-a-chip platform with innate immunity enables identification of angiopoietin-1 derived peptide as a therapeutic for SARS-CoV-2 induced inflammation.
  8. Picturing of the Lung Tumor Cellular Composition by Multispectral Flow Cytometry.
  9. Metabolic labeling of secreted matrix to investigate cell-material interactions in tissue engineering and mechanobiology.
  10. Tertiary lymphoid structures and their association to immune phenotypes and circulatory IL2 levels in pancreatic ductal adenocarcinoma.
  11. Tumor microenvironments in 3D.
  12. CXCL12 promotes CCR7 ligand-mediated breast cancer cell invasion and migration toward lymphatic vessels.
  1. Cancer Discov. 2022 Feb 11.
    Fungal Mycobiome Drives IL33 Secretion and TH2 Infiltration in PDAC.
      Mutant KRAS promotes type 2 immunity through upregulation of IL33 in pancreatic ductal adenocarcinoma (PDAC).
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-024
  2. Oncoimmunology. 2022 ;11(1): 2027136
    Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity.
    Yuan-Na Lin, Marcel O Schmidt, Ghada M Sharif, Eveline E Vietsch, Amber J Kiliti, Megan E Barefoot, Anna T Riegel, Anton Wellstein.
      Pancreatic cancer remains largely unresponsive to immune modulatory therapy attributable in part to an immunosuppressive, desmoplastic tumor microenvironment. Here, we analyze mechanisms of cancer cell-autonomous resistance to T cells. We used a 3D co-culture model of cancer cell spheroids from the KPC (LSL-KrasG12D/+ /LSL-Trp53R172H/+ /p48-Cre) pancreatic ductal adenocarcinoma (PDAC) model, to examine interactions with tumor-educated T cells isolated from draining lymph nodes of PDAC-bearing mice. Subpopulations of cancer cells resistant to these tumor-educated T cells were isolated from the in vitro co-culture and their properties compared with sensitive cancer cells. In co-culture with resistant cancer cell subpopulations, tumor-educated T cells showed reduced effector T cell functionality, reduced infiltration into tumor cell spheroids and decreased induction of apoptosis. A combination of comparative transcriptomic analyses, cytometric and immunohistochemistry techniques allowed us to dissect the role of differential gene expression and signaling pathways between sensitive and resistant cells. A decreased expression of the chemokine CXCL12 (SDF-1) was revealed as a common feature in the resistant cell subpopulations. Adding back CXCL12 reversed the resistant phenotype and was inhibited by the CXCR4 inhibitor AMD3100 (plerixafor). We conclude that reduced CXCL12 signaling contributes to PDAC subpopulation resistance to T cell-mediated attack.
    Keywords:  T cell resistance; chemokines; co-culture; cytotoxicity; pancreatic cancer
    DOI:  https://doi.org/10.1080/2162402X.2022.2027136
  3. Cancer Discov. 2022 Feb 11.
    Multikinase Inhibition Induces Tumor Microenvironment Remodeling in PDAC.
      Combination trametinib and nintedanib induces cell death and reprograms the immunosuppressive microenvironment.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-026
  4. Cancer Discov. 2022 Feb;12(2): 296-298
    The Few yet Fabp4ulous Pancreatic Stellate Cells Give Rise to Protumoral CAFs.
    Edna Cukierman.
      Cancer-associated fibroblast (CAF) pro- and anti-pancreatic cancer functional dichotomy has been at the center of numerous studies. In this issue of Cancer Discovery, Helms and colleagues demonstrate that although pancreatic stellate cell-derived CAFs constitute a desmoplastic cell minority, these cells play a protumorigenic role via microenvironmental mechanomodulation.See related article by Helms et al., p. 484.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1501
  5. Nat Commun. 2022 Feb 09. 13(1): 759
    The induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression.
    Anne E Geller, Rejeena Shrestha, Matthew R Woeste, Haixun Guo, Xiaoling Hu, Chuanlin Ding, Kalina Andreeva, Julia H Chariker, Mingqian Zhou, David Tieri, Corey T Watson, Robert A Mitchell, Huang-Ge Zhang, Yan Li, Robert C G Martin Ii, Eric C Rouchka, Jun Yan.
      Despite the remarkable success of immunotherapy in many types of cancer, pancreatic ductal adenocarcinoma has yet to benefit. Innate immune cells are critical to anti-tumor immunosurveillance and recent studies have revealed that these populations possess a form of memory, termed trained innate immunity, which occurs through transcriptomic, epigenetic, and metabolic reprograming. Here we demonstrate that yeast-derived particulate β-glucan, an inducer of trained immunity, traffics to the pancreas, which causes a CCR2-dependent influx of monocytes/macrophages to the pancreas that display features of trained immunity. These cells can be activated upon exposure to tumor cells and tumor-derived factors, and show enhanced cytotoxicity against pancreatic tumor cells. In orthotopic models of pancreatic ductal adenocarcinoma, β-glucan treated mice show significantly reduced tumor burden and prolonged survival, which is further enhanced when combined with immunotherapy. These findings characterize the dynamic mechanisms and localization of peripheral trained immunity and identify an application of trained immunity to cancer.
    DOI:  https://doi.org/10.1038/s41467-022-28407-4
  6. Nat Rev Drug Discov. 2022 Feb 09.
    Blocking breast cancer metastasis.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-022-00026-0
  7. Lab Chip. 2022 Feb 10.
    Vasculature-on-a-chip platform with innate immunity enables identification of angiopoietin-1 derived peptide as a therapeutic for SARS-CoV-2 induced inflammation.
    Rick Xing Ze Lu, Benjamin Fook Lun Lai, Naimeh Rafatian, Dakota Gustafson, Scott B Campbell, Arinjay Banerjee, Robert Kozak, Karen Mossman, Samira Mubareka, Kathryn L Howe, Jason E Fish, Milica Radisic.
      Coronavirus disease 2019 (COVID-19) was primarily identified as a novel disease causing acute respiratory syndrome. However, as the pandemic progressed various cases of secondary organ infection and damage by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported, including a breakdown of the vascular barrier. As SARS-CoV-2 gains access to blood circulation through the lungs, the virus is first encountered by the layer of endothelial cells and immune cells that participate in host defense. Here, we developed an approach to study SARS-CoV-2 infection using vasculature-on-a-chip. We first modeled the interaction of virus alone with the endothelialized vasculature-on-a-chip, followed by the studies of the interaction of the virus exposed-endothelial cells with peripheral blood mononuclear cells (PBMCs). In an endothelial model grown on a permeable microfluidic bioscaffold under flow conditions, both human coronavirus (HCoV)-NL63 and SARS-CoV-2 presence diminished endothelial barrier function by disrupting VE-cadherin junctions and elevating the level of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8, and angiopoietin-2. Inflammatory cytokine markers were markedly more elevated upon SARS-CoV-2 infection compared to HCoV-NL63 infection. Introduction of PBMCs with monocytes into the vasculature-on-a-chip upon SARS-CoV-2 infection further exacerbated cytokine-induced endothelial dysfunction, demonstrating the compounding effects of inter-cellular crosstalk between endothelial cells and monocytes in facilitating the hyperinflammatory state. Considering the harmful effects of SARS-CoV-2 on endothelial cells, even without active virus proliferation inside the cells, a potential therapeutic approach is critical. We identified angiopoietin-1 derived peptide, QHREDGS, as a potential therapeutic capable of profoundly attenuating the inflammatory state of the cells consistent with the levels in non-infected controls, thereby improving the barrier function and endothelial cell survival against SARS-CoV-2 infection in the presence of PBMC.
    DOI:  https://doi.org/10.1039/d1lc00817j
  8. Front Immunol. 2022 ;13 827719
    Picturing of the Lung Tumor Cellular Composition by Multispectral Flow Cytometry.
    Catherine Olesch, David Brunn, Öznur Aktay-Cetin, Evelyn Sirait-Fischer, Soni Savai Pullamsetti, Friedrich Grimminger, Werner Seeger, Bernhard Brüne, Andreas Weigert, Rajkumar Savai.
      The lung tumor microenvironment plays a critical role in the tumorigenesis and metastasis of lung cancer, resulting from the crosstalk between cancer cells and microenvironmental cells. Therefore, comprehensive identification and characterization of cell populations in the complex lung structure is crucial for development of novel targeted anti-cancer therapies. Here, a hierarchical clustering approach with multispectral flow cytometry was established to delineate the cellular landscape of murine lungs under steady-state and cancer conditions. Fluorochromes were used multiple times to be able to measure 24 cell surface markers with only 13 detectors, yielding a broad picture for whole-lung phenotyping. Primary and metastatic murine lung tumor models were included to detect major cell populations in the lung, and to identify alterations to the distribution patterns in these models. In the primary tumor models, major altered populations included CD324+ epithelial cells, alveolar macrophages, dendritic cells, and blood and lymph endothelial cells. The number of fibroblasts, vascular smooth muscle cells, monocytes (Ly6C+ and Ly6C-) and neutrophils were elevated in metastatic models of lung cancer. Thus, the proposed clustering approach is a promising method to resolve cell populations from complex organs in detail even with basic flow cytometers.
    Keywords:  hierarchical clustering; lung cancer; lung tumor heterogeneity; multispectral flow cytometry; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.827719
  9. Nat Protoc. 2022 Feb 09.
    Metabolic labeling of secreted matrix to investigate cell-material interactions in tissue engineering and mechanobiology.
    Claudia Loebel, Aya M Saleh, Kathryn R Jacobson, Ryan Daniels, Robert L Mauck, Sarah Calve, Jason A Burdick.
      Re-creating features of the native extracellular matrix (ECM) with engineered biomaterials has become a valuable tool to probe the influence of ECM properties on cellular functions (e.g., differentiation) and toward the engineering of tissues. However, characterization of newly secreted (nascent) matrix and turnover, which are important in the context of cells interacting with these biomaterials, has been limited by a lack of tools. We developed a protocol to visualize and quantify the spatiotemporal evolution of newly synthesized and deposited matrix by cells that are either cultured atop (2D) or embedded within (3D) biomaterial systems (e.g., hydrogels, fibrous matrices). This technique relies on the incorporation of a noncanonical amino acid (azidohomoalanine) into proteins as they are synthesized. Deposited nascent ECM components are then visualized with fluorescent cyclooctynes via copper-free cycloaddition for spatiotemporal analysis or modified with cleavable biotin probes for identification. Here we describe the preparation of hyaluronic acid hydrogels through ultraviolet or visible light induced cross-linking for 2D and 3D cell culture, as well as the fluorescent labeling of nascent ECM deposited by cells during culture. We also provide protocols for secondary immunofluorescence of specific ECM components and ImageJ-based ECM quantification methods. Hyaluronic acid polymer synthesis takes 2 weeks to complete, and hydrogel formation for 2D or 3D cell culture is performed in 2-3 h. Lastly, we detail the identification of nascent proteins, including enrichment, preparation and analysis with mass spectrometry, which can be completed in 10 d.
    DOI:  https://doi.org/10.1038/s41596-021-00652-9
  10. Oncoimmunology. 2022 ;11(1): 2027148
    Tertiary lymphoid structures and their association to immune phenotypes and circulatory IL2 levels in pancreatic ductal adenocarcinoma.
    Azaz Ahmed, Sophia Köhler, Rosa Klotz, Nathalia Giese, Thilo Hackert, Christoph Springfeld, Inka Zörnig, Dirk Jäger, Niels Halama.
      Pancreatic ductal adenocarcinoma (PDA) is usually unresponsive to immunotherapeutic approaches. However, tertiary lymphoid structures (TLS) are associated with favorable patient outcomes in PDA. A better understanding of the B cell infiltrate and biological features of TLS formation is needed to further explore their potential and improve patient management. We analyzed tumor tissues (n = 55) and corresponding blood samples (n = 51) from PDA patients by systematical immunohistochemistry and multiplex cytokine measurements. The tissue was compartmentalized in "tumor" and "stroma" and separately examined. Clinical patient information was used to perform survival analyses. We found that the mere number of B cells is not associated with patient survival, but formation of TLS in the peritumoral stroma is a prognostic favorable marker in PDA patients. TLS-positive tissues show a higher density of CD8+ T cells and CD20+ B cells and a higher IL2 level in the peritumoral stroma than tissues without TLS. Compartmental assessment shows that gradients of IL2 expression differ with regard to TLS formation: TLS presence is associated with higher IL2 levels in the stromal than in the tumoral compartment, while no difference is seen in patients without TLS. Focusing on the stroma-to-serum gradient, only patients without TLS show significantly higher IL2 levels in the serum than in stroma. Finally, low circulatory IL2 levels are associated with local TLS formation. Our findings highlight that TLS are prognostic favorable and associated with antitumoral features in the microenvironment of PDA. Also, we propose easily accessible serum IL2 levels as a potential marker for TLS prediction.
    Keywords:  Interleukin-2; Pancreatic ductal adenocarcinoma; Tertiary lymphoid structures
    DOI:  https://doi.org/10.1080/2162402X.2022.2027148
  11. Nat Methods. 2022 Feb;19(2): 138
    Tumor microenvironments in 3D.
    Madhura Mukhopadhyay.
      
    DOI:  https://doi.org/10.1038/s41592-022-01402-9
  12. Cancer Sci. 2022 Feb 08.
    CXCL12 promotes CCR7 ligand-mediated breast cancer cell invasion and migration toward lymphatic vessels.
    Haruko Hayasaka, Junichi Yoshida, Yasutaka Kuroda, Akihiro Nishiguchi, Michiya Matsusaki, Kei Kishimoto, Hitoshi Nishimura, Mari Okada, Yuki Shimomura, Daichi Kobayashi, Yoshihito Shimazu, Yuji Taya, Mitsuru Akashi, Masayuki Miyasaka.
      Chemokines are a family of cytokines that mediate leukocyte trafficking and are involved in tumor cell migration, growth, and progression. Although there is emerging evidence that multiple chemokines are expressed in tumor tissues and that each chemokine induces receptor-mediated signaling, their collaboration to regulate tumor invasion and lymph node metastasis has not been fully elucidated. In this study, we examined the effect of CXCL12 on the CCR7-dependent signaling in MDA-MB-231 human breast cancer cells to determine the role of CXCL12 and CCR7 ligand chemokines in breast cancer metastasis to lymph nodes. CXCL12 enhanced the CCR7-dependent in vitro chemotaxis and cell invasion into collagen gels at suboptimal concentrations of CCL21. CXCL12 promoted CCR7 homodimer formation, ligand binding, CCR7 accumulation into membrane ruffles, and cell response at lower concentrations of CCL19. Immunohistochemistry of MDA-MB-231-derived xenograft tumors revealed that CXCL12 is primarily located in the peri-cellular matrix surrounding tumor cells, whereas the CCR7 ligand, CCL21, mainly associates with LYVE-1+ intra-tumoral and peritumoral lymphatic vessels. In the three-dimensional tumor invasion model with lymph networks, CXCL12 stimulation facilitates breast cancer cell migration to CCL21-reconstituted lymphatic networks. These results indicate that CXCL12/CXCR4 signaling promotes breast cancer cell migration and invasion toward CCR7 ligand-expressing intra-tumoral lymphatic vessels and supports CCR7 signaling associated with lymph node metastasis.
    Keywords:  Chemokine; breast cancer; invasion; lymph node; metastasis
    DOI:  https://doi.org/10.1111/cas.15293
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