bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021‒08‒08
eleven papers selected by
Philipp Albrecht
Friedrich Schiller University
  1. Apoptosis in the Pancreatic Cancer Tumor Microenvironment-The Double-Edged Sword of Cancer-Associated Fibroblasts.
  2. A Microfluidic 3D Endothelium-on-a-Chip Model to Study Transendothelial Migration of T Cells in Health and Disease.
  3. Collagen Organization Does Not Influence T-Cell Distribution in Stroma of Human Pancreatic Cancer.
  4. Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer.
  5. Simulating drug concentrations in PDMS microfluidic organ chips.
  6. Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma.
  7. Targeting the Stroma in the Management of Pancreatic Cancer.
  8. CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion.
  9. Identification and Validation of Immune Molecular Subtypes in Pancreatic Ductal Adenocarcinoma: Implications for Prognosis and Immunotherapy.
  10. In Vitro Strategies to Vascularize 3D Physiologically Relevant Models.
  11. CD8+ T Cell Exhaustion in Cancer.
  1. Cells. 2021 Jul 01. pii: 1653. [Epub ahead of print]10(7):
    Apoptosis in the Pancreatic Cancer Tumor Microenvironment-The Double-Edged Sword of Cancer-Associated Fibroblasts.
    Ester Pfeifer, Joy M Burchell, Francesco Dazzi, Debashis Sarker, Richard Beatson.
      Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF.
    Keywords:  CAF; PDAC; TME; apoptosis; fibroblasts; pancreatic cancer; stroma; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells10071653
  2. Int J Mol Sci. 2021 Jul 30. pii: 8234. [Epub ahead of print]22(15):
    A Microfluidic 3D Endothelium-on-a-Chip Model to Study Transendothelial Migration of T Cells in Health and Disease.
    Luuk de Haan, Johnny Suijker, Ruthger van Roey, Nina Berges, Elissaveta Petrova, Karla Queiroz, Wouter Strijker, Thomas Olivier, Oliver Poeschke, Sakshi Garg, Lenie J van den Broek.
      The recruitment of T cells is a crucial component in the inflammatory cascade of the body. The process involves the transport of T cells through the vascular system and their stable arrest to vessel walls at the site of inflammation, followed by extravasation and subsequent infiltration into tissue. Here, we describe an assay to study 3D T cell dynamics under flow in real time using a high-throughput, artificial membrane-free microfluidic platform that allows unimpeded extravasation of T cells. We show that primary human T cells adhere to endothelial vessel walls upon perfusion of microvessels and can be stimulated to undergo transendothelial migration (TEM) by TNFα-mediated vascular inflammation and the presence of CXCL12 gradients or ECM-embedded melanoma cells. Notably, migratory behavior was found to differ depending on T cell activation states. The assay is unique in its comprehensiveness for modelling T cell trafficking, arrest, extravasation and migration, all in one system, combined with its throughput, quality of imaging and ease of use. We envision routine use of this assay to study immunological processes and expect it to spur research in the fields of immunological disorders, immuno-oncology and the development of novel immunotherapeutics.
    Keywords:  T cell; extravasation; high-throughput; immuno-oncology; in vitro; inflammation; microfluidic; organ-on-a-chip; transendothelial migration
    DOI:  https://doi.org/10.3390/ijms22158234
  3. Cancers (Basel). 2021 Jul 21. pii: 3648. [Epub ahead of print]13(15):
    Collagen Organization Does Not Influence T-Cell Distribution in Stroma of Human Pancreatic Cancer.
    Eva-Maria Kamionka, Baifeng Qian, Wolfgang Gross, Frank Bergmann, Thilo Hackert, Carlo A Beretta, Nicolas Dross, Eduard Ryschich.
      The dominant intrastromal T-cell infiltration in pancreatic cancer is mainly caused by the contact guidance through the excessive desmoplastic reaction and could represent one of the obstacles to an effective immune response in this tumor type. This study analyzed the collagen organization in normal and malignant pancreatic tissues as well as its influence on T-cell distribution in pancreatic cancer. Human pancreatic tissue was analyzed using immunofluorescence staining and multiphoton and SHG microscopy supported by multistep image processing. The influence of collagen alignment on activated T-cells was studied using 3D matrices and time-lapse microscopy. It was found that the stroma of malignant and normal pancreatic tissues was characterized by complex individual organization. T-cells were heterogeneously distributed in pancreatic cancer and there was no relationship between T-cell distribution and collagen organization. There was a difference in the angular orientation of collagen alignment in the peritumoral and tumor-cell-distant stroma regions in the pancreatic ductal adenocarcinoma tissue, but there was no correlation in the T-cell densities between these regions. The grade of collagen alignment did not influence the directionality of T-cell migration in the 3D collagen matrix. It can be concluded that differences in collagen organization do not change the spatial orientation of T-cell migration or influence stromal T-cell distribution in human pancreatic cancer. The results of the present study do not support the rationale of remodeling of stroma collagen organization for improvement of T-cell-tumor cell contact in pancreatic ductal adenocarcinoma.
    Keywords:  T-cell infiltration; chemokines; collagen organization; human pancreatic cancer; tumor stroma
    DOI:  https://doi.org/10.3390/cancers13153648
  4. Front Cell Dev Biol. 2021 ;9 655152
    Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer.
    Xinglong Geng, Hongze Chen, Liang Zhao, Jisheng Hu, Wenbo Yang, Guanqun Li, Chundong Cheng, Zhongjie Zhao, Tao Zhang, Le Li, Bei Sun.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA) high interleukin-6 (IL-6) low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMA low IL-6 high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.
    Keywords:  cancer-associated fibroblasts; diagnosis; hallmark; heterogeneity; pancreatic cancer; prognosis; therapy
    DOI:  https://doi.org/10.3389/fcell.2021.655152
  5. Lab Chip. 2021 Aug 04.
    Simulating drug concentrations in PDMS microfluidic organ chips.
    Jennifer Grant, Alican Özkan, Crystal Oh, Gautam Mahajan, Rachelle Prantil-Baun, Donald E Ingber.
      Microfluidic organ-on-a-chip (Organ Chip) cell culture devices are often fabricated using polydimethylsiloxane (PDMS) because it is biocompatible, transparent, elastomeric, and oxygen permeable; however, hydrophobic small molecules can absorb to PDMS, which makes it challenging to predict drug responses. Here, we describe a combined simulation and experimental approach to predict the spatial and temporal concentration profile of a drug under continuous dosing in a PDMS Organ Chip containing two parallel channels separated by a porous membrane that is lined with cultured cells, without prior knowledge of its log P value. First, a three-dimensional finite element model of drug loss into the chip was developed that incorporates absorption, adsorption, convection, and diffusion, which simulates changes in drug levels over time and space as a function of potential PDMS diffusion coefficients and log P values. By then experimentally measuring the diffusivity of the compound in PDMS and determining its partition coefficient through mass spectrometric analysis of the drug concentration in the channel outflow, it is possible to estimate the effective log P range of the compound. The diffusion and partition coefficients were experimentally derived for the antimalarial drug and potential SARS-CoV-2 therapeutic, amodiaquine, and incorporated into the model to quantitatively estimate the drug-specific concentration profile over time measured in human lung airway chips lined with bronchial epithelium interfaced with pulmonary microvascular endothelium. The same strategy can be applied to any device geometry, surface treatment, or in vitro microfluidic model to simulate the spatial and temporal gradient of a drug in 3D without prior knowledge of the partition coefficient or the rate of diffusion in PDMS. Thus, this approach may expand the use of PDMS Organ Chip devices for various forms of drug testing.
    DOI:  https://doi.org/10.1039/d1lc00348h
  6. Cells. 2021 Jul 19. pii: 1821. [Epub ahead of print]10(7):
    Plasma Metabolome Profiling Identifies Metabolic Subtypes of Pancreatic Ductal Adenocarcinoma.
    Ujjwal Mukund Mahajan, Ahmed Alnatsha, Qi Li, Bettina Oehrle, Frank-Ulrich Weiss, Matthias Sendler, Marius Distler, Waldemar Uhl, Tim Fahlbusch, Elisabetta Goni, Georg Beyer, Ansgar Chromik, Markus Bahra, Fritz Klein, Christian Pilarsky, Robert Grützmann, Markus M Lerch, Kirsten Lauber, Nicole Christiansen, Beate Kamlage, Ivonne Regel, Julia Mayerle.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP® Global Profiling and MxP® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.
    Keywords:  complex lipids; metabolic subtypes; pancreatic ductal adenocarcinoma; sphingolipids
    DOI:  https://doi.org/10.3390/cells10071821
  7. Front Oncol. 2021 ;11 691185
    Targeting the Stroma in the Management of Pancreatic Cancer.
    Penelope Edwards, Byung Woog Kang, Ian Chau.
      Pancreatic cancer (PC) presents extremely aggressive tumours and is associated with poor survival. This is attributed to the unique features of the tumour microenvironment (TME), which is known to create a dense stromal formation and poorly immunogenic condition. In particular, the TME of PC, including the stromal cells and extracellular matrix, plays an essential role in the progression and chemoresistance of PC. Consequently, several promising agents that target key components of the stroma have already been developed and are currently in multiple stages of clinical trials. Therefore, the authors review the latest available evidence on novel stroma-targeting approaches, highlighting the potential impact of the stroma as a key component of the TME in PC.
    Keywords:  SPARC; bruton kinase inhibitor; hedgehog (Hh); hyaluronic acid; immune checkpoint inhibition (ICI); pancreatic cancer; stroma
    DOI:  https://doi.org/10.3389/fonc.2021.691185
  8. Front Oncol. 2021 ;11 668349
    CAFs Interacting With TAMs in Tumor Microenvironment to Enhance Tumorigenesis and Immune Evasion.
    Gurcan Gunaydin.
      Cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) are among the most important and abundant players of the tumor microenvironment. CAFs as well as TAMs are known to play pivotal supportive roles in tumor growth and progression. The number of CAF or TAM cells is mostly correlated with poor prognosis. Both CAFs and TAMs are in a reciprocal communication with the tumor cells in the tumor milieu. In addition to such interactions, CAFs and TAMs are also involved in a dynamic and reciprocal interrelationship with each other. Both CAFs and TAMs are capable of altering each other's functions. Here, the current understanding of the distinct mechanisms about the complex interplay between CAFs and TAMs are summarized. In addition, the consequences of such a mutual relationship especially for tumor progression and tumor immune evasion are highlighted, focusing on the synergistic pleiotropic effects. CAFs and TAMs are crucial components of the tumor microenvironment; thus, they may prove to be potential therapeutic targets. A better understanding of the tri-directional interactions of CAFs, TAMs and cancer cells in terms of tumor progression will pave the way for the identification of novel theranostic cues in order to better target the crucial mechanisms of carcinogenesis.
    Keywords:  M1/M2 cells; cancer associated fibroblasts; macrophage polarization; monocytes; tumor associated macrophages; tumor biology; tumor immunology; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.668349
  9. Front Immunol. 2021 ;12 690056
    Identification and Validation of Immune Molecular Subtypes in Pancreatic Ductal Adenocarcinoma: Implications for Prognosis and Immunotherapy.
    Ruiyu Li, Yangzhige He, Hui Zhang, Jing Wang, Xiaoding Liu, Hangqi Liu, Huanwen Wu, Zhiyong Liang.
      Background: Pancreatic ductal adenocarcinoma (PDAC) remains treatment refractory. Immunotherapy has achieved success in the treatment of multiple malignancies. However, the efficacy of immunotherapy in PDAC is limited by a lack of promising biomarkers. In this research, we aimed to identify robust immune molecular subtypes of PDAC to facilitate prognosis prediction and patient selection for immunotherapy.Methods: A training cohort of 149 PDAC samples from The Cancer Genome Atlas (TCGA) with mRNA expression data was analyzed. By means of non-negative matrix factorization (NMF), we virtually dissected the immune-related signals from bulk gene expression data. Detailed immunogenomic and survival analyses of the immune molecular subtypes were conducted to determine their biological and clinical relevance. Validation was performed in five independent datasets on a total of 615 samples.
    Results: Approximately 31% of PDAC samples (46/149) had higher immune cell infiltration, more active immune cytolytic activity, higher activation of the interferon pathway, a higher tumor mutational burden (TMB), and fewer copy number alterations (CNAs) than the other samples (all P < 0.001). This new molecular subtype was named Immune Class, which served as an independent favorable prognostic factor for overall survival (hazard ratio, 0.56; 95% confidence interval, 0.33-0.97). Immune Class in cooperation with previously reported tumor and stroma classifications had a cumulative effect on PDAC prognostic stratification. Moreover, programmed cell death-1 (PD-1) inhibitors showed potential efficacy for Immune Class (P = 0.04). The robustness of our immune molecular subtypes was further verified in the validation cohort.
    Conclusions: By capturing immune-related signals in the PDAC tumor microenvironment, we reveal a novel molecular subtype, Immune Class. Immune Class serves as an independent favorable prognostic factor for overall survival in PDAC patients.
    Keywords:  immune molecular subtypes; immunogenomics; immunotherapy; non-negative matrix factorization; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.3389/fimmu.2021.690056
  10. Adv Sci (Weinh). 2021 Aug 05. e2100798
    In Vitro Strategies to Vascularize 3D Physiologically Relevant Models.
    Alessandra Dellaquila, Chau Le Bao, Didier Letourneur, Teresa Simon-Yarza.
      Vascularization of 3D models represents a major challenge of tissue engineering and a key prerequisite for their clinical and industrial application. The use of prevascularized models built from dedicated materials could solve some of the actual limitations, such as suboptimal integration of the bioconstructs within the host tissue, and would provide more in vivo-like perfusable tissue and organ-specific platforms. In the last decade, the fabrication of vascularized physiologically relevant 3D constructs has been attempted by numerous tissue engineering strategies, which are classified here in microfluidic technology, 3D coculture models, namely, spheroids and organoids, and biofabrication. In this review, the recent advancements in prevascularization techniques and the increasing use of natural and synthetic materials to build physiological organ-specific models are discussed. Current drawbacks of each technology, future perspectives, and translation of vascularized tissue constructs toward clinics, pharmaceutical field, and industry are also presented. By combining complementary strategies, these models are envisioned to be successfully used for regenerative medicine and drug development in a near future.
    Keywords:  3D cell culture; bioprinting; microfluidics; tissue engineering; vascularization
    DOI:  https://doi.org/10.1002/advs.202100798
  11. Front Immunol. 2021 ;12 715234
    CD8+ T Cell Exhaustion in Cancer.
    Joseph S Dolina, Natalija Van Braeckel-Budimir, Graham D Thomas, Shahram Salek-Ardakani.
      A paradigm shift in the understanding of the exhausted CD8+ T cell (Tex) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8+ Tex is composed of multiple interconnected subpopulations. The heterogeneity within the CD8+ Tex lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively. These populations occupy distinct peripheral and intratumoral niches and are characterized by transcriptional processes that govern transitions between cell states. This review presents key findings in the field to construct an updated view of the spatial, transcriptional, and functional heterogeneity of anti-tumoral CD8+ Tex. These emerging insights broadly call for (re-)focusing cancer immunotherapies to center on the driver mechanism(s) underlying the CD8+ Tex developmental continuum aimed at stabilizing functional subsets.
    Keywords:  CXCR3; PD-1/PD-L1; T cell exhaustion; T cell trafficking; cancer immunotherapy; co-stimulatory/inhibitory receptors; stem-like CD8+ T cells; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2021.715234
This page is being maintained by Thomas Krichel. It was last updated on 2021‒08‒13 at 11:03:23.