bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2021–11–14
seven papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth.
  2. Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models.
  3. Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes, Cancer-Associated Fibroblasts, and CD200 in Pancreatic Cancer.
  4. Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance.
  5. Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma.
  6. Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.
  7. Single-cell RNA sequencing to characterize the response of pancreatic cancer to anti-PD-1 immunotherapy.
  1. Cancers (Basel). 2021 Oct 24. pii: 5338. [Epub ahead of print]13(21):
    IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth.
    Jiahui Li, Xiaolin Wu, Lars Schiffmann, Thomas MacVicar, Chenghui Zhou, Zhefang Wang, Dai Li, Oscar Velazquez Camacho, Reiner Heuchel, Margarete Odenthal, Axel Hillmer, Alexander Quaas, Yue Zhao, Christiane J Bruns, Felix C Popp.
      In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.
    Keywords:  IL17B/RB; metabolism; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13215338
  2. Front Cell Dev Biol. 2021 ;9 741162
    Pancreatic Ductal Adenocarcinoma: Preclinical in vitro and ex vivo Models.
    Beate Gündel, Xinyuan Liu, Matthias Löhr, Rainer Heuchel.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most overlooked cancers despite its dismal median survival time of 6 months. The biggest challenges in improving patient survival are late diagnosis due to lack of diagnostic markers, and limited treatment options due to almost complete therapy resistance. The past decades of research identified the dense stroma and the complex interplay/crosstalk between the cancer- and the different stromal cells as the main culprits for the slow progress in improving patient outcome. For better ex vivo simulation of this complex tumor microenvironment the models used in PDAC research likewise need to become more diverse. Depending on the focus of the investigation, several in vitro and in vivo models for PDAC have been established in the past years. Particularly, 3D cell culture such as spheroids and organoids have become more frequently used. This review aims to examine current PDAC in vitro models, their inherent limitations, and their successful implementations in research.
    Keywords:  3D cell culture; organoids; pancreatic ductal adenocarcinoma; reporter assays; spheroid
    DOI:  https://doi.org/10.3389/fcell.2021.741162
  3. Cancers (Basel). 2021 Nov 02. pii: 5501. [Epub ahead of print]13(21):
    Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes, Cancer-Associated Fibroblasts, and CD200 in Pancreatic Cancer.
    Tyler MacNeil, Ioannis A Vathiotis, Saba Shafi, Thazin Nwe Aung, Jon Zugazagoitia, Aaron M Gruver, Kyla Driscoll, David L Rimm.
      Pancreatic cancer is marked by a desmoplastic tumor microenvironment and low tumor immunogenicity, making it difficult for immunotherapy drugs to improve outcomes for patients. Tumor-infiltrating lymphocytes (TILs) and cancer-associated fibroblasts (CAFs) are seen in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma (PDAC). In this work, we sought to characterize the expression levels and potential prognostic value of TILs (CD4, CD8, and CD20) and CAFs (Thy-1, FAP, and SMA) in a large retrospective cohort of PDAC patients. Additionally, we investigated the expression levels and prognostic significance of CD200, an immunoinhibitory protein that has shown interest as a potential target for immune checkpoint blockade. We measured the expression levels of these seven proteins with multiplexed immunofluorescence staining and quantitative immunofluorescence (QIF). We found CD8 and FAP to be independent predictors of progression-free survival and overall survival. CD200 was found to be heterogeneously expressed in both the tumor and stromal compartments of PDAC, with the majority of patients having positive stromal expression and negative tumor expression. This work demonstrates the potential clinical utility of CD8 and FAP in PDAC patients, and it sheds light on the expression patterns of CD200 in pancreatic cancer as the protein is being tested as a target for immune checkpoint blockade.
    Keywords:  CD200; PDAC; fibroblasts; immunotherapy; lymphocytes
    DOI:  https://doi.org/10.3390/cancers13215501
  4. Cancers (Basel). 2021 Nov 04. pii: 5532. [Epub ahead of print]13(21):
    Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance.
    Kostas Palamaris, Evangelos Felekouras, Stratigoula Sakellariou.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells exhibiting cancer stem cells (CSCs) phenotype. In this review we summarize the available data on the signaling cascades regulating EMT and the molecular isnteractions between pancreatic cancer and stromal cells that activate them. In addition, we provide a link between EMT, tumor progression, and chemoresistance in PDAC.
    Keywords:  cancer stem cells; chemoresistance; epithelial to mesenchymal transition; intratumor heterogeneity; pancreatic ductal adenocarcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13215532
  5. BMC Cancer. 2021 Nov 10. 21(1): 1197
    Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma.
    Sachie Kiryu, Zensho Ito, Machi Suka, Tsuuse Bito, Shin Kan, Kan Uchiyama, Masayuki Saruta, Taigo Hata, Yuki Takano, Shuichi Fujioka, Takeyuki Misawa, Takashi Yamauchi, Hiroyuki Yanagisawa, Nobuhiro Sato, Toshifumi Ohkusa, Haruo Sugiyama, Shigeo Koido.
       BACKGROUND: Both activated tumor-infiltrating lymphocytes (TILs) and immune-suppressive cells, such as regulatory T cells (Tregs), in the tumor microenvironment (TME) play an important role in the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC).
    METHODS: The densities of TILs, programmed death receptor 1 (PD-1) + T cells, and forkhead box P3 (Foxp3) + T cells were analyzed by immunohistochemical staining. The associations of the immunological status of the PDAC microenvironment with overall survival (OS) time and disease-free survival (DFS) time were evaluated.
    RESULTS: PDAC patients with a high density of TILs in the TME or PD-1-positive T cells in tertiary lymphoid aggregates (TLAs) demonstrated a significantly better prognosis than those with a low density of TILs or PD-1-negativity, respectively. Moreover, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than those with low levels of Foxp3-expressing T cells. Importantly, even with a high density of the TILs in TME or PD-1-positive T cells in TLAs, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than patients with low levels of Foxp3-expressing T cells. A PDAC TME with a high density of TILs/high PD-1 positivity/low Foxp3 expression was an independent predictive marker associated with superior prognosis.
    CONCLUSION: Combined assessment of TILs, PD-1+ cells, and Foxp3+ T cells in the TME may predict the prognosis of PDAC patients following surgical resection.
    Keywords:  Foxp3; Immune-related cells; PD-1; Pancreatic cancer; Prognosis; Surgical resection; TIL
    DOI:  https://doi.org/10.1186/s12885-021-08911-4
  6. Nat Metab. 2021 Nov 11.
    Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.
    Simon Schwörer, Natalya N Pavlova, Francesco V Cimino, Bryan King, Xin Cai, Gina M Sizemore, Craig B Thompson.
      The aberrant production of collagen by fibroblasts is a hallmark of many solid tumours and can influence cancer progression. How the mesenchymal cells in the tumour microenvironment maintain their production of extracellular matrix proteins as the vascular delivery of glutamine and glucose becomes compromised remains unclear. Here we show that pyruvate carboxylase (PC)-mediated anaplerosis in tumour-associated fibroblasts contributes to tumour fibrosis and growth. Using cultured mesenchymal and cancer cells, as well as mouse allograft models, we provide evidence that extracellular lactate can be utilized by fibroblasts to maintain tricarboxylic acid (TCA) cycle anaplerosis and non-essential amino acid biosynthesis through PC activity. Furthermore, we show that fibroblast PC is required for collagen production in the tumour microenvironment. These results establish TCA cycle anaplerosis as a determinant of extracellular matrix collagen production, and identify PC as a potential target to inhibit tumour desmoplasia.
    DOI:  https://doi.org/10.1038/s42255-021-00480-x
  7. Transl Oncol. 2021 Nov 09. pii: S1936-5233(21)00253-9. [Epub ahead of print]15(1): 101262
    Single-cell RNA sequencing to characterize the response of pancreatic cancer to anti-PD-1 immunotherapy.
    Jing Zhou, Yuexu Jiang, Yue Huang, Qiongling Wang, Jussuf T Kaifi, Eric T Kimchi, Chiswili Yves Chabu, Zhenguo Liu, Trupti Joshi, Guangfu Li.
      Pancreatic cancer (PaC) is resistant to immune checkpoint therapy, but the underlying mechanisms are largely unknown. In this study, we have established four orthotopic PaC murine models with different PaC cell lines by intra-pancreatic inoculation. Therapeutic examinations demonstrate that only tumors induced with Panc02-H7 cells respond to αPD-1 antibody treatment, leading to significantly reduced tumor growth and increased survival in the recipient mice. Transcriptomic profiling at a single-cell resolution characterizes the molecular activity of different cells within tumors. Comparative analysis and validated experiments demonstrate that αPD-1-sensitive and -resistant tumors differently shape the immune landscape in the tumor microenvironment (TME) and markedly altering effector CD8+ T cells and tumor-associated macrophages (TAMs) in their number, frequency, and gene profile. More exhausted effector CD8+ T cells and increased M2-like TAMs with a reduced capacity of antigen presentation are detected in resistant Panc02-formed tumors versus responsive Panc02-H7-formed tumors. Together, our data highlight the correlation of tumor-induced imbalance of macrophages with the fate of tumor-resident effector CD8+ T cells and PaC response to αPD-1 immunotherapy. TAMs as a critical regulator of tumor immunity and immunotherapy contribute to PaC resistance to immune checkpoint blockade.
    Keywords:  Pancreatic cancer (PaC); Programmed cell death protein 1 (PD-1); Single-cell sequencing (scRNA-seq); Tumor-associated macrophages (TAM); αPD-1 antibody (αPD-1 Ab)
    DOI:  https://doi.org/10.1016/j.tranon.2021.101262
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