bims-tuchim Biomed News
on Tumor-on-chip models
Issue of 2022–01–30
six papers selected by
Philipp Albrecht, Friedrich Schiller University
  1. Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion.
  2. SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer.
  3. Human endothelial cells in high glucose: New clues from culture in 3D microfluidic chips.
  4. Engineering tumor stromal mechanics for improved T cell therapy.
  5. Emerging Prospects for the Study of Colorectal Cancer Stem Cells using Patient-Derived Organoids.
  6. The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma.
  1. Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01731-9. [Epub ahead of print]38(4): 110227
    Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion.
    Elizabeth R Murray, Shinelle Menezes, Jack C Henry, Josie L Williams, Lorena Alba-Castellón, Priththivika Baskaran, Ivan Quétier, Ami Desai, Jacqueline J T Marshall, Ian Rosewell, Marianthi Tatari, Vinothini Rajeeve, Faraz Khan, Jun Wang, Panoraia Kotantaki, Eleanor J Tyler, Namrata Singh, Claire S Reader, Edward P Carter, Kairbaan Hodivala-Dilke, Richard P Grose, Hemant M Kocher, Nuria Gavara, Oliver Pearce, Pedro Cutillas, John F Marshall, Angus J M Cameron.
      In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) can both promote and suppress tumor progression. Here, we show that the Rho effector protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 is associated with reduced PSC proliferation, contractility, and alpha-smooth muscle actin (α-SMA) stress fibers. In spheroid co-cultures with PDAC cells, loss of PKN2 prevents PSC invasion but, counter-intuitively, promotes invasive cancer cell outgrowth. PKN2 deletion induces a myofibroblast to inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. Further, deletion of PKN2 in the pancreatic stroma induces more locally invasive, orthotopic pancreatic tumors. Finally, we demonstrate that a PKN2KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast function can limit important stromal tumor-suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.
    Keywords:  CAF; PKN2; Rho GTPases; cancer-associated fibroblasts; matrisome; pancreatic cancer; protein kinase N2; tumour microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2021.110227
  2. Cancer Lett. 2022 Jan 22. pii: S0304-3835(22)00042-8. [Epub ahead of print]
    SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer.
    Tian-Jiao Li, Kai-Zhou Jin, Hao Li, Long-Yun Ye, Peng-Cheng Li, Bruce Jiang, Xuan Lin, Zhen-Yu Liao, Hui-Ru Zhang, Sai-Meng Shi, Meng-Xiong Lin, Qing-Lin Fei, Zhi-Wen Xiao, Hua-Xiang Xu, Liang Liu, Xian-Jun Yu, Wei-Ding Wu.
      Pancreatic ductal adenocarcinoma (PDAC) usually presents infrequent infiltration of T lymphocytes. The known immune-checkpoint inhibitors to date focus on activating T cells and manifest limited effectiveness in PDAC. SIGLEC15 was identified as a novel tumor-associated macrophage (TAM)-related immune-checkpoint in other cancer types, while its immunosuppressive role and clinical significance remained unclear in PDAC. In our study, SIGLEC15 presented immunosuppressive relevance in PDAC via bioinformatic analysis and expressed on TAM and PDAC cells. SIGLEC15+ TAM, rather than SIGLEC15+ PDAC cells or SIGLEC15- TAM, correlated with poor prognosis and immunosuppressive microenvironment in the PDAC microarray cohort. Compared with SIGLEC15- TAM, SIGLEC15+ TAM presented an M2-like phenotype that could be modulated by SIGLEC15 in a tumor cell-dependent manner. In mechanism, SIGLEC15 interacted with PDAC-expressed sialic acid, preferentially α-2, 3 sialic acids, to stimulate SYK phosphorylation in TAM, which further promoted its immunoregulatory cytokines and chemokines production. In vivo, SIGLEC15+ TAM also presented an M2-like phenotype, accelerated tumor growth, and facilitated immunosuppressive microenvironment, which was greatly abolished by SYK inhibitor. Our study highlighted a novel M2-promoting function of SIGLEC15 and strongly suggested SIGLEC15 as a potential immunotherapeutic target for PDAC.
    Keywords:  PDAC; SIGLEC15; SYK; Sialic acid; TAM
    DOI:  https://doi.org/10.1016/j.canlet.2022.01.026
  3. FASEB J. 2022 Feb;36(2): e22137
    Human endothelial cells in high glucose: New clues from culture in 3D microfluidic chips.
    Laura Locatelli, Mehdi Inglebert, Roberta Scrimieri, Priti Kumari Sinha, Gian Vincenzo Zuccotti, Paolo Milani, Lionel Bureau, Chaouqi Misbah, Jeanette A M Maier.
      Several studies have demonstrated the role of high glucose in promoting endothelial dysfunction utilizing traditional two-dimensional (2D) culture systems, which, however, do not replicate the complex organization of the endothelium within a vessel constantly exposed to flow. Here we describe the response to high glucose of micro- and macro-vascular human endothelial cells (EC) cultured in biomimetic microchannels fabricated through soft lithography and perfused to generate shear stress. In 3D macrovascular EC exposed to a shear stress of 0.4 Pa respond to high glucose with cytoskeletal remodeling and alterations in cell shape. Under the same experimental conditions, these effects are more pronounced in microvascular cells that show massive cytoskeletal disassembly and apoptosis after culture in high glucose. However, when exposed to a shear stress of 4 Pa, which is physiological in the microvasculature, human dermal microvascular endothelial cells (HDMEC) show alterations of the cytoskeleton but no apoptosis. This result emphasizes the sensitivity of HDMEC to different regimens of flow. No significant variations in the thickness of glycocalyx were detected in both human endothelial cells from the umbilical vein and HDMEC exposed to high glucose in 3D, whereas clear differences emerge between cells cultured in static 2D versus microfluidic channels. We conclude that culture in microfluidic microchannels unveils unique insights into endothelial dysfunction by high glucose.
    Keywords:  cytoskeleton; diabetes; endothelium; glucose; microfluidics; microvasculature on a chip
    DOI:  https://doi.org/10.1096/fj.202100914R
  4. Biochim Biophys Acta Gen Subj. 2022 Jan 22. pii: S0304-4165(22)00013-7. [Epub ahead of print] 130095
    Engineering tumor stromal mechanics for improved T cell therapy.
    Linxuan Ying, Mahsa Yazdani, Richard Koya, Ruogang Zhao.
      Adoptive cellular therapies (ACT), including the engineered T cell receptor (TCR) therapy and chimeric antigen receptor (CAR) T Cell Therapy, are currently at the forefront of cancer immunotherapy. However, their efficacy for the treatment of solid tumors has not been confirmed. The fibrotic stroma surrounding the solid tumor has been suggested as a main barrier in the disarmament and suppression of the engineered T cells. In this review, we will discuss the recent findings on the mechanism of T cell suppression by the tumor stroma with a special emphasis on the effect of stromal mechanics. We will also discuss the engineering approaches used to dissect the mechanism of the T cell suppression by the stromal mechanical factors. Finally, we will provide a future outlook on the strategies to improve the efficacy of T cell therapy through altering the tumor stromal fibrosis.
    DOI:  https://doi.org/10.1016/j.bbagen.2022.130095
  5. Curr Cancer Drug Targets. 2022 Jan 17.
    Emerging Prospects for the Study of Colorectal Cancer Stem Cells using Patient-Derived Organoids.
    Ling Ding, Yuning Yang, Qin Lu, Zhiyun Cao, Nathaniel Weygant.
      Human colorectal cancer (CRC) patient-derived organoids (PDOs) are a powerful ex vivo platform to directly assess the impact of molecular alterations and therapies on tumor cell proliferation, differentiation, response to chemotherapy, tumor-microenvironment interactions, and other facets of CRC biology. Next-generation sequencing studies have demonstrated that CRC is a highly heterogeneous disease with multiple distinct subtypes. PDOs are a promising new tool to study CRC due to their ability to accurately recapitulate their source tumor and thus reproduce this heterogeneity. This review summarizes the state-of-the-art for CRC PDOs in the study of cancer stem cells (CSCs) and the cancer stem cell niche. Areas of focus include the relevance of PDOs to understanding CSC-related paracrine signaling, identifying interactions between CSCs and the tumor microenvironment, and modeling CSC-driven resistance to chemotherapies and targeted therapies. Finally, we summarize current findings regarding the identification and verification of CSC targets using PDOs and their potential use in personalized medicine.
    Keywords:  Colorectal cancer; LGR5; cancer stem cells; patient-derived organoids; personalized medicine; tumor microenvironment
    DOI:  https://doi.org/10.2174/1568009622666220117124546
  6. Front Cell Dev Biol. 2021 ;9 821232
    The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma.
    Xuefei Liu, Ziwei Luo, Xuechen Ren, Zhihang Chen, Xiaoqiong Bao, Jianghua Zheng, Zhixiang Zuo.
      Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies. Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups. Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy. Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.
    Keywords:  cell-cell communication; immunocyte infiltration; immunotherapy; pancreatic ductal adenocarcinoma; single cell RNA-seq
    DOI:  https://doi.org/10.3389/fcell.2021.821232
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