bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–07–18
thirteen papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. Engineering Breast Cancer On-chip-Moving Toward Subtype Specific Models.
  2. Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment.
  3. Organotypic Slice Cultures as Preclinical Models of Tumor Microenvironment in Primary Pancreatic Cancer and Metastasis.
  4. Pancreatic cancer chemotherapy is potentiated by induction of tertiary lymphoid structures in mice.
  5. Cancer metabolism: looking forward.
  6. The interplay between matrix deformation and the coordination of turning events governs directed neutrophil migration in 3D matrices.
  7. Immunity-Related Gene Signature Identifies Subtypes Benefitting From Adjuvant Chemotherapy or Potentially Responding to PD1/PD-L1 Blockage in Pancreatic Cancer.
  8. Automatic Pancreatic Ductal Adenocarcinoma Detection in Whole Slide Images Using Deep Convolutional Neural Networks.
  9. DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism.
  10. Rapid diagnosis and tumor margin assessment during pancreatic cancer surgery with the MasSpec Pen technology.
  11. Differently PEGylated Polymer Nanoparticles for Pancreatic Cancer Delivery: Using a Novel Near-Infrared Emissive and Biodegradable Polymer as the Fluorescence Tracer.
  12. Expression and Role of Heparan Sulfated Proteoglycans in Pancreatic Cancer.
  13. Hypoxia-alleviated nanoplatform to enhance chemosensitivity and sonodynamic effect in pancreatic cancer.
  1. Front Bioeng Biotechnol. 2021 ;9 694218
    Engineering Breast Cancer On-chip-Moving Toward Subtype Specific Models.
    Carmen Moccia, Kristina Haase.
      Breast cancer is the second leading cause of death among women worldwide, and while hormone receptor positive subtypes have a clear and effective treatment strategy, other subtypes, such as triple negative breast cancers, do not. Development of new drugs, antibodies, or immune targets requires significant re-consideration of current preclinical models, which frequently fail to mimic the nuances of patient-specific breast cancer subtypes. Each subtype, together with the expression of different markers, genetic and epigenetic profiles, presents a unique tumor microenvironment, which promotes tumor development and progression. For this reason, personalized treatments targeting components of the tumor microenvironment have been proposed to mitigate breast cancer progression, particularly for aggressive triple negative subtypes. To-date, animal models remain the gold standard for examining new therapeutic targets; however, there is room for in vitro tools to bridge the biological gap with humans. Tumor-on-chip technologies allow for precise control and examination of the tumor microenvironment and may add to the toolbox of current preclinical models. These new models include key aspects of the tumor microenvironment (stroma, vasculature and immune cells) which have been employed to understand metastases, multi-organ interactions, and, importantly, to evaluate drug efficacy and toxicity in humanized physiologic systems. This review provides insight into advanced in vitro tumor models specific to breast cancer, and discusses their potential and limitations for use as future preclinical patient-specific tools.
    Keywords:  breast cancer; microfluidics; preclinical model; tumor microenvironment; tumor-on-chip
    DOI:  https://doi.org/10.3389/fbioe.2021.694218
  2. Nat Rev Cancer. 2021 Jul 09.
    Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment.
    Samuel A Kerk, Thales Papagiannakopoulos, Yatrik M Shah, Costas A Lyssiotis.
      Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.
    DOI:  https://doi.org/10.1038/s41568-021-00375-9
  3. J Vis Exp. 2021 Jun 22.
    Organotypic Slice Cultures as Preclinical Models of Tumor Microenvironment in Primary Pancreatic Cancer and Metastasis.
    Rüdiger Braun, Olha Lapshyna, Susanne Eckelmann, Kim Honselmann, Louisa Bolm, Meike Ten Winkel, Steffen Deichmann, Oliver Schilling, Charli Kruse, Tobias Keck, Ulrich Wellner, Peter Bronsert, Matthias Brandenburger.
      Realistic preclinical models of primary pancreatic cancer and metastasis are urgently needed to test the therapy response ex vivo and facilitate personalized patient treatment. However, the absence of tumor-specific microenvironment in currently used models, e.g., patient-derived cell lines and xenografts, only allows limited predictive insights. Organotypic slice cultures (OTSCs) comprise intact multicellular tissue, which can be rapidly used for the spatially resolved drug response testing. This protocol describes the generation and cultivation of viable tumor slices of pancreatic cancer and its metastasis. Briefly, tissue is casted in low melt agarose and stored in cold isotonic buffer. Next, tissue slices of 300 µm thickness are generated with a vibratome. After preparation, slices are cultured at an air-liquid interface using cell culture inserts and an appropriate cultivation medium. During cultivation, changes in cell differentiation and viability can be monitored. Additionally, this technique enables the application of treatment to viable human tumor tissue ex vivo and subsequent downstream analyses, such as transcriptome and proteome profiling. OTSCs provide a unique opportunity to test the individual treatment response ex vivo and identify individual transcriptomic and proteomic profiles associated with the respective response of distinct slices of a tumor. OTSCs can be further explored to identify therapeutic strategies to personalize treatment of primary pancreatic cancer and metastasis.
    DOI:  https://doi.org/10.3791/62541
  4. Cell Mol Gastroenterol Hepatol. 2021 Jul 09. pii: S2352-345X(21)00138-7. [Epub ahead of print]
    Pancreatic cancer chemotherapy is potentiated by induction of tertiary lymphoid structures in mice.
    Francesca R Delvecchio, Rachel E A Fincham, Sarah Spear, Andrew Clear, Marina Roy-Luzarraga, Frances R Balkwill, John G Gribben, Michele Bombardieri, Kairbaan Hodivala-Dilke, Melania Capasso, Hemant M Kocher.
       BACKGROUND AND AIMS: The presence of tertiary lymphoid structures (TLS) may confer survival benefit to patients with pancreatic ductal adenocarcinoma (PDAC), in an otherwise immunologically inert malignancy. Yet, the precise role in PDAC has not been elucidated. Here we aim to investigate the structure and role of TLS in human and murine pancreatic cancer.
    METHODS: Multicolor immunofluorescence and immunohistochemistry was used to fully characterize TLS in human and murine (transgenic - KPC: KrasG12D, p53R172H, Pdx-1-Cre - and orthotopic) pancreatic cancer. An orthotopic murine model was developed to study the development of TLS and the effect of the combined chemotherapy and immunotherapy on tumor growth.
    RESULTS: Mature, functional TLS are not ubiquitous in human PDAC and KPC murine cancers and are absent in the orthotopic murine model. TLS formation can be induced in the orthotopic model of PDAC after intra-tumoral injection of lymphoid chemokines (CXCL13/CCL21). Co-administration of systemic chemotherapy (gemcitabine) and intra-tumoral lymphoid chemokines into orthotopic tumors altered immune cell infiltration facilitating TLS induction and potentiating anti-tumor activity of chemotherapy. This resulted in significant tumor reduction, an effect not achieved by either treatment alone. Anti-tumor activity seen after TLS induction is associated with B cell-mediated dendritic cell activation.
    CONCLUSION: This study provides supportive evidence that TLS induction may potentiate the anti-tumor activity of chemotherapy in a murine model of PDAC. A detailed understanding of TLS kinetics and their induction, due to multiple host and tumor factors may help design personalized therapies harnessing the potential of immuno-oncology.
    Keywords:  B cells; T cells; dendritic cells; orthotopic; transgenic mice
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.06.023
  5. Nat Rev Cancer. 2021 Jul 16.
    Cancer metabolism: looking forward.
    Inmaculada Martínez-Reyes, Navdeep S Chandel.
      Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Cancer cells autonomously alter their flux through various metabolic pathways in order to meet the increased bioenergetic and biosynthetic demand as well as mitigate oxidative stress required for cancer cell proliferation and survival. Cancer driver mutations coupled with environmental nutrient availability control flux through these metabolic pathways. Metabolites, when aberrantly accumulated, can also promote tumorigenesis. The development and application of new technologies over the last few decades has not only revealed the heterogeneity and plasticity of tumours but also allowed us to uncover new metabolic pathways involved in supporting tumour growth. The tumour microenvironment (TME), which can be depleted of certain nutrients, forces cancer cells to adapt by inducing nutrient scavenging mechanisms to sustain cancer cell proliferation. There is growing appreciation that the metabolism of cell types other than cancer cells within the TME, including endothelial cells, fibroblasts and immune cells, can modulate tumour progression. Because metastases are a major cause of death of patients with cancer, efforts are underway to understand how metabolism is harnessed by metastatic cells. Additionally, there is a new interest in exploiting cancer genetic analysis for patient stratification and/or dietary interventions in combination with therapies that target metabolism. In this Perspective, we highlight these main themes that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing questions that remain unanswered.
    DOI:  https://doi.org/10.1038/s41568-021-00378-6
  6. Sci Adv. 2021 Jul;pii: eabf3882. [Epub ahead of print]7(29):
    The interplay between matrix deformation and the coordination of turning events governs directed neutrophil migration in 3D matrices.
    Joshua François, Adithan Kandasamy, Yi-Ting Yeh, Amy Schwartz, Cindy Ayala, Ruedi Meili, Shu Chien, Juan C Lasheras, Juan C Del Álamo.
      Neutrophils migrating through extravascular spaces must negotiate narrow matrix pores without losing directional movement. We investigated how chemotaxing neutrophils probe matrices and adjust their migration to collagen concentration ([col]) changes by tracking 20,000 cell trajectories and quantifying cell-generated 3D matrix deformations. In low-[col] matrices, neutrophils exerted large deformations and followed straight trajectories. As [col] increased, matrix deformations decreased, and neutrophils turned often to circumvent rather than remodel matrix pores. Inhibiting protrusive or contractile forces shifted this transition to lower [col], implying that mechanics play a crucial role in defining migratory strategies. To balance frequent turning and directional bias, neutrophils used matrix obstacles as pivoting points to steer toward the chemoattractant. The Actin Related Protein 2/3 complex coordinated successive turns, thus controlling deviations from chemotactic paths. These results offer an improved understanding of the mechanisms and molecular regulators used by neutrophils during chemotaxis in restrictive 3D environments.
    DOI:  https://doi.org/10.1126/sciadv.abf3882
  7. Front Cell Dev Biol. 2021 ;9 682261
    Immunity-Related Gene Signature Identifies Subtypes Benefitting From Adjuvant Chemotherapy or Potentially Responding to PD1/PD-L1 Blockage in Pancreatic Cancer.
    Hao Qian, Hongzhe Li, Junjie Xie, Xiongxiong Lu, Fanlu Li, Weishen Wang, Xiaomei Tang, Minmin Shi, Linxi Jiang, Hongwei Li, Hao Chen, Chenghong Peng, Zhiwei Xu, Xiaxing Deng, Baiyong Shen.
      Tumor microenvironment comprises of a variety of cell types, which is quite complex and involved in chemotherapy and immune checkpoint blockage resistance. In order to explore the mechanisms involved in tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC), we first constructed an immunity-related 18-gene signature using The Cancer Genome Atlas (TCGA) PDAC project data. Then we applied the 18-gene signature to divide PDAC patients into low score and high score groups. Patients in high score group showed inferior prognosis, which was validated in another four independent cohorts, including Ruijin cohort. High score group showed significant enrichment of pathways involved in cell division and cell cycle especially in G1/S phase transition. In high score group, IHC analysis revealed higher levels of the proliferative indexes of Ki67 and PCNA than that in low score group. Prognostic analysis confirmed that patients in high score group could benefit from the gemcitabine-based adjuvant chemotherapy. In low score group, the programmed cell death 1 ligand 1(PD-L1) (+) cases showed worse prognosis but higher T cell infiltration than PD-L1(-) cases. Our immunity-related 18-gene signature could effectively predict PDAC prognosis, and it might be a practical predictive tool to identify PDAC subtype benefitting from gemcitabine-based adjuvant chemotherapy or potentially responding to PD1/PD-L1 blockade therapy.
    Keywords:  gene signature; immunity; pancreatic cancer; pancreatic ductal adenocarcinoma; prognosis
    DOI:  https://doi.org/10.3389/fcell.2021.682261
  8. Front Oncol. 2021 ;11 665929
    Automatic Pancreatic Ductal Adenocarcinoma Detection in Whole Slide Images Using Deep Convolutional Neural Networks.
    Hao Fu, Weiming Mi, Boju Pan, Yucheng Guo, Junjie Li, Rongyan Xu, Jie Zheng, Chunli Zou, Tao Zhang, Zhiyong Liang, Junzhong Zou, Hao Zou.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancer types worldwide, with the lowest 5-year survival rate among all kinds of cancers. Histopathology image analysis is considered a gold standard for PDAC detection and diagnosis. However, the manual diagnosis used in current clinical practice is a tedious and time-consuming task and diagnosis concordance can be low. With the development of digital imaging and machine learning, several scholars have proposed PDAC analysis approaches based on feature extraction methods that rely on field knowledge. However, feature-based classification methods are applicable only to a specific problem and lack versatility, so that the deep-learning method is becoming a vital alternative to feature extraction. This paper proposes the first deep convolutional neural network architecture for classifying and segmenting pancreatic histopathological images on a relatively large WSI dataset. Our automatic patch-level approach achieved 95.3% classification accuracy and the WSI-level approach achieved 100%. Additionally, we visualized the classification and segmentation outcomes of histopathological images to determine which areas of an image are more important for PDAC identification. Experimental results demonstrate that our proposed model can effectively diagnose PDAC using histopathological images, which illustrates the potential of this practical application.
    Keywords:  convolutional neural network; deep learning; histology; pancreatic ductal adenocarcinoma (PDAC); whole-slide image analysis
    DOI:  https://doi.org/10.3389/fonc.2021.665929
  9. Cell Death Dis. 2021 Jul 15. 12(7): 705
    DHA exhibits synergistic therapeutic efficacy with cisplatin to induce ferroptosis in pancreatic ductal adenocarcinoma via modulation of iron metabolism.
    Jing Du, Xu Wang, Yanchun Li, Xueying Ren, Yi Zhou, Wanye Hu, Chaoting Zhou, Qiangan Jing, Chen Yang, Luyang Wang, Huanjuan Li, Lijuan Fang, Yonglie Zhou, Xiangmin Tong, Ying Wang.
      Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal cancer with limited treatment options. Cisplatin (DDP) is used as a mainstay of chemotherapeutic agents in combination with other drugs or radiotherapy for PDAC therapy. However, DDP exhibits severe side-effects that can lead to discontinuation of therapy, and the acquired drug resistance of tumor cells presents serious clinical obstacles. Therefore, it is imperative to develop a more effective and less toxic therapeutic strategy. We and others have previously discovered that dihydroartemisinin (DHA) represents a safe and promising therapeutic agent to preferentially induce cancer cell ferroptosis. In the present study, we find that DHA could intensively strengthen the cytotoxicity of DDP and significantly reduce its effective concentrations both in vitro and in vivo. Combination of DHA and DDP synergistically inhibits the proliferation and induces DNA damage of PDAC cells. Mechanically, the combinative treatment impairs mitochondrial homeostasis, characterized by destroyed mitochondrial morphology, decreased respiratory capacity, reduced ATP production, and accumulated mitochondria-derived ROS. Further studies show that ferroptosis contributes to the cytotoxic effects in PDAC cells under the challenge of DHA and DDP, together with catastrophic accumulation of free iron and unrestricted lipid peroxidation. Moreover, pharmacologic depleting of the free iron reservoir or reconstituted expression of FTH contributes to the tolerance of DHA/DDP-induced ferroptosis, while iron addition accelerates the ferroptotic cell death. In summary, these results provide experimental evidence that DHA acts synergistically with DDP and renders PDAC cells vulnerable to ferroptosis, which may act as a promising therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41419-021-03996-y
  10. Proc Natl Acad Sci U S A. 2021 Jul 13. pii: e2104411118. [Epub ahead of print]118(28):
    Rapid diagnosis and tumor margin assessment during pancreatic cancer surgery with the MasSpec Pen technology.
    Mary E King, Jialing Zhang, John Q Lin, Kyana Y Garza, Rachel J DeHoog, Clara L Feider, Alena Bensussan, Marta Sans, Anna Krieger, Sunil Badal, Michael F Keating, Spencer Woody, Sadhna Dhingra, Wendong Yu, Christopher Pirko, Kirtan A Brahmbhatt, George Van Buren, William E Fisher, James Suliburk, Livia S Eberlin.
      Intraoperative delineation of tumor margins is critical for effective pancreatic cancer surgery. Yet, intraoperative frozen section analysis of tumor margins is a time-consuming and often challenging procedure that can yield confounding results due to histologic heterogeneity and tissue-processing artifacts. We have previously described the development of the MasSpec Pen technology as a handheld mass spectrometry-based device for nondestructive tissue analysis. Here, we evaluated the usefulness of the MasSpec Pen for intraoperative diagnosis of pancreatic ductal adenocarcinoma based on alterations in the metabolite and lipid profiles in in vivo and ex vivo tissues. We used the MasSpec Pen to analyze 157 banked human tissues, including pancreatic ductal adenocarcinoma, pancreatic, and bile duct tissues. Classification models generated from the molecular data yielded an overall agreement with pathology of 91.5%, sensitivity of 95.5%, and specificity of 89.7% for discriminating normal pancreas from cancer. We built a second classifier to distinguish bile duct from pancreatic cancer, achieving an overall accuracy of 95%, sensitivity of 92%, and specificity of 100%. We then translated the MasSpec Pen to the operative room and predicted on in vivo and ex vivo data acquired during 18 pancreatic surgeries, achieving 93.8% overall agreement with final postoperative pathology reports. Notably, when integrating banked tissue data with intraoperative data, an improved agreement of 100% was achieved. The result obtained demonstrate that the MasSpec Pen provides high predictive performance for tissue diagnosis and compatibility for intraoperative use, suggesting that the technology may be useful to guide surgical decision-making during pancreatic cancer surgeries.
    Keywords:  MasSpec Pen; mass spectrometry; pancreatic cancer; surgical margin evaluation
    DOI:  https://doi.org/10.1073/pnas.2104411118
  11. Front Bioeng Biotechnol. 2021 ;9 699610
    Differently PEGylated Polymer Nanoparticles for Pancreatic Cancer Delivery: Using a Novel Near-Infrared Emissive and Biodegradable Polymer as the Fluorescence Tracer.
    Huazhong Cai, Yanxia Chen, Liusheng Xu, Yingping Zou, Xiaoliang Zhou, Guoxin Liang, Dongqing Wang, Zhimin Tao.
      In this study, a chemically synthetic polymer, benzo[1,2-b:4,5-b']difuran(BDF)-based donor-acceptor copolymer PBDFDTBO, was individually coated by amphiphilic poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-PCL) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol) (DSPE-PEG or PEG-DSPE), to form stably fluorescent nanoparticles in the near-infrared (NIR) window. The physicochemical properties of the synthesized nanoparticles were characterized and compared, including their size, surface charge, and morphology. In addition, in vitro studies were also performed using two pancreatic cancer cell lines, assessing the cell viability of the PBDFDTBO-included PEGylated nanoparticles formulations. Moreover, in vivo studies were also conducted, using subcutaneous murine cancer models to investigate the polymeric nanoparticles' circulation time, tumor accumulation, and preferred organ biodistribution. The overall results demonstrated that even with the same PEGylated surface, the hydrophobic composition anchored on the encapsulated PBDFDTBO core strongly affected the biodistribution and tumor accumulation of the nanoparticles, to a degree possibly determined by the hydrophobic interactions between the hydrophobic segment of amphiphilic polymers (DSPE or PCL moiety) and the enwrapped PBDFDTBO. Both PEGylated nanoparticles were compared to obtain an optimized coating strategy for a desired biological feature in pancreatic cancer delivery.
    Keywords:  PEGylation; nanoparticles; near-infrared fluorescence imaging; pancreatic cancer; polymer
    DOI:  https://doi.org/10.3389/fbioe.2021.699610
  12. Front Oncol. 2021 ;11 695858
    Expression and Role of Heparan Sulfated Proteoglycans in Pancreatic Cancer.
    Simone Furini, Chiara Falciani.
      Pancreatic cancer is a lethal condition with poor outcomes and an increasing incidence. The unfavourable prognosis is due to the lack of early symptoms and consequent late diagnosis. An effective method for the early diagnosis of pancreatic cancer is therefore sought by many researchers in the field. Heparan sulfated proteoglycan-related genes are often expressed differently in tumors than in normal tissues. Alteration of the tumor microenvironment is correlated with the ability of heparan sulfated proteoglycans to bind cytokines and growth factors and eventually to influence tumor progression. Here we discuss the importance of glypicans, syndecans, perlecan and extracellular matrix modifying enzymes, such as heparanases and sulfatases, as potential diagnostics in pancreatic cancer. We also ran an analysis on a multidimensional cancer genomics database for heparan sulfated proteoglycan-related genes, and report altered expression of some of them.
    Keywords:  cancer genomics; heparan sulfated proteoglycans; pancreatic cancer; precision medicine; prognosis; screening
    DOI:  https://doi.org/10.3389/fonc.2021.695858
  13. Cancer Lett. 2021 Jul 08. pii: S0304-3835(21)00335-9. [Epub ahead of print]520 100-108
    Hypoxia-alleviated nanoplatform to enhance chemosensitivity and sonodynamic effect in pancreatic cancer.
    Jifan Chen, Yuheng Bao, Yue Song, Cong Zhang, Fuqiang Qiu, Yu Sun, Lei Xin, Jing Cao, Yifan Jiang, Jiali Luo, Chao Zhang, Guowei Wang, Qunyin Li, Yajing Liu, Weijun Tong, Pintong Huang.
      Pancreatic cancer is a severe disease that threatens human health. The hypoxic tumor microenvironment in pancreatic cancer leads to resistance to conventional therapies and helps to maintain tumor malignancy. First-line drugs present the disadvantage of systemic side effects, and a synergistic method with sonodynamic therapy (SDT) has been established as an emerging approach. In this study, we produced hypoxia-alleviating nanoplatforms (denoted as PZGI NPs) with zeolitic imidazolate frameworks-90 (ZIF-90) nanoparticles nucleating on platinum (Pt) nanoparticles and co-loaded with gemcitabine and IR780. This platform can catalyze peroxide to oxygen with loaded Pt nanoparticles to alleviate tumor hypoxia. Moreover, the loaded drugs could be quickly released in the lysosome microenvironment, which has a low pH value and high ATP level microenvironment in the mitochondria. This strategy could enhance the sensitivity of cancer cells to chemotherapy. Further, under ultrasound exposure, it could transfer the produced oxygen into a highly cytotoxic singlet oxygen for the augmented sonodynamic effect. Therefore, this multifunctional hypoxia-alleviating nanoplatform offers a promising strategy for chemo-sonodynamic therapy against pancreatic cancer.
    Keywords:  Nanozyme; Pancreatic ductal cell carcinoma; Sonodynamic therapy; Zeolitic imidazolate frameworks-90
    DOI:  https://doi.org/10.1016/j.canlet.2021.07.008
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