bims-tuchim 2021-04-25 papers

bims-tuchim

Biomed News

on Tumor-on-chip models

Issue of 2021–04–25
ten papers selected by
Philipp Albrecht, Friedrich Schiller University

Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins.
Modeling human pancreatic ductal adenocarcinoma for translational research: current options, challenges, and prospective directions.
Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells.
Engineering Hydrogels for Personalized Disease Modeling and Regenerative Medicine.
Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.
Tissue-specific parameters for the design of ECM-mimetic biomaterials.
On-Chip Replication of Extremely Early-Stage Tumor Behavior.
Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel.
Immune cell shuttle for precise delivery of nanotherapeutics for heart disease and cancer.
Extracellular matrix and its therapeutic potential for cancer treatment.

Front Immunol. 2021 ;12 612271

Stroma Involvement in Pancreatic Ductal Adenocarcinoma: An Overview Focusing on Extracellular Matrix Proteins.

Sophie Liot, Jonathan Balas, Alexandre Aubert, Laura Prigent, Perrine Mercier-Gouy, Bernard Verrier, Philippe Bertolino, Ana Hennino, Ulrich Valcourt, Elise Lambert.

  Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide and is predicted to become second in 2030 in industrialized countries if no therapeutic progress is made. Among the different types of pancreatic cancers, Pancreatic Ductal Adenocarcinoma (PDAC) is by far the most represented one with an occurrence of more than 90%. This specific cancer is a devastating malignancy with an extremely poor prognosis, as shown by the 5-years survival rate of 2-9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Pancreatic tumors progress with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. This malignancy is characterized by an extremely dense stroma deposition around lesions, accompanied by tissue hypovascularization and a profound immune suppression. Altogether, these combined features make access to cancer cells almost impossible for conventional chemotherapeutics and new immunotherapeutic agents, thus contributing to the fatal outcomes of the disease. Initially ignored, the Tumor MicroEnvironment (TME) is now the subject of intensive research related to PDAC treatment and could contain new therapeutic targets. In this review, we will summarize the current state of knowledge in the field by focusing on TME composition to understand how this specific compartment could influence tumor progression and resistance to therapies. Attention will be paid to Tenascin-C, a matrix glycoprotein commonly upregulated during cancer that participates to PDAC progression and thus contributes to poor prognosis.

Keywords:  extracellular matrix; pancreatic ductal adenocarcinoma; stroma; tenascin; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.612271
Ann Pancreat Cancer. 2020 Dec;pii: 17. [Epub ahead of print]3

Modeling human pancreatic ductal adenocarcinoma for translational research: current options, challenges, and prospective directions.

Reecha Suri, Jacquelyn W Zimmerman, Richard A Burkhart.

  Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with one of the lowest survival rates. Early detection, an improved understanding of tumor biology, and novel therapeutic discoveries are needed in order to improve overall patient survival. Scientific progress towards meeting these goals relies upon accurate modeling of the human disease. From two-dimensional (2D) cell lines to the advanced modeling available today, we aim to characterize the critical tools in efforts to further understand PDAC biology. The National Center for Biotechnology Information's PubMed and the Elsevier's SCOPUS were used to perform a comprehensive literature review evaluating preclinical human-derived PDAC models. Keywords included pancreatic cancer, PDAC, preclinical models, KRAS mutations, xenograft, co-culturing fibroblasts, co-culturing lymphocytes and PDAC immunotherapy Initial search was limited to articles about PDAC and was then expanded to include other gastrointestinal malignancies where information may complement our effort. A supervised review of the key literature's references was utilized to augment the capture of relevant data. The discovery and refinement of techniques enabling immortalized 2D cell culture provided the cornerstone for modern cancer biology research. Cell lines have been widely used to represent PDAC in vitro but are limited in capacity to model three-dimensional (3D) tumor attributes and interactions within the tumor microenvironment. Xenografts are an alternative method to model PDAC with improved capacity to understand certain aspects of 3D tumor biology in vivo while limited by the use of immunodeficient mice. Advances of in vitro modeling techniques have led to 3D organoid models for PDAC biology. Co-culturing models in the 3D environment have been proposed as an efficient modeling system for improving upon the limitations encountered in the standard 2D and xenograft tumor models. The integrated network of cells and stroma that comprise PDAC in vivo need to be accurately depicted ex vivo to continue to make progress in this disease. Recapitulating the complex tumor microenvironment in a preclinical model of human disease is an outstanding and urgent need in PDAC. Definitive characterization of available human models for PDAC serves to further the core mission of pancreatic cancer translational research.

Keywords:  Pancreatic cancer; organoids; precision medicine; tumor models

DOI:  https://doi.org/10.21037/apc-20-29
Nat Commun. 2021 Apr 20. 12(1): 2328

Suppression of pancreatic ductal adenocarcinoma growth and metastasis by fibrillar collagens produced selectively by tumor cells.

Chenxi Tian, Ying Huang, Karl R Clauser, Steffen Rickelt, Allison N Lau, Steven A Carr, Matthew G Vander Heiden, Richard O Hynes.

Pancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens.

DOI: https://doi.org/10.1038/s41467-021-22490-9
Acta Biomater. 2021 Apr 18. pii: S1742-7061(21)00257-9. [Epub ahead of print]

Engineering Hydrogels for Personalized Disease Modeling and Regenerative Medicine.

Ian M Tayler, Ryan S Stowers.

  Technological innovations and advances in scientific understanding have created an environment where data can be collected, analyzed, and interpreted at scale, ushering in the era of personalized medicine. The ability to isolate cells from individual patients offers tremendous promise if those cells can be used to generate functional tissue replacements or used in disease modeling to determine optimal treatment strategies. Here, we review recent progress in the use of hydrogels to create artificial cellular microenvironments for personalized tissue engineering and regenerative medicine applications, as well as to develop personalized disease models. We highlight engineering strategies to control stem cell fate through hydrogel design, and the use of hydrogels in combination with organoids, advanced imaging methods, and novel bioprinting techniques to generate functional tissues. We also discuss the use of hydrogels to study molecular mechanisms underlying diseases and to create personalized in vitro disease models to complement existing pre-clinical models. Continued progress in the development of engineered hydrogels, in combination with other emerging technologies, will be essential to realize the immense potential of personalized medicine. Statement of Significance: In this review, we cover recent advances in hydrogel engineering strategies with applications in personalized medicine. Specifically, we focus on material systems to expand or control differentiation of patient-derived stem cells, and hydrogels to reprogram somatic cells to pluripotent states. We then review applications of hydrogels in developing personalized engineered tissues. We also highlight the use of hydrogel systems as personalized disease models, focusing on specific examples in fibrosis and cancer, and more broadly on drug screening strategies using patient-derived cells and hydrogels. We believe this review will be a valuable contribution to the Special Issue and the readership of Acta Biomaterialia will appreciate the comprehensive overview of the utility of hydrogels in the developing field of personalized medicine.

Keywords:  Disease modeling; Hydrogels; Personalized medicine; Tissue engineering

DOI:  https://doi.org/10.1016/j.actbio.2021.04.020
Cell Rep. 2021 Apr 20. pii: S2211-1247(21)00323-5. [Epub ahead of print]35(3): 109009

Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity.

Neus Bota-Rabassedas, Priyam Banerjee, Yichi Niu, Wenjian Cao, Jiayi Luo, Yuanxin Xi, Xiaochao Tan, Kuanwei Sheng, Young-Ho Ahn, Sieun Lee, Edwin Roger Parra, Jaime Rodriguez-Canales, Jacob Albritton, Michael Weiger, Xin Liu, Hou-Fu Guo, Jiang Yu, B Leticia Rodriguez, Joshua J A Firestone, Barbara Mino, Chad J Creighton, Luisa M Solis, Pamela Villalobos, Maria Gabriela Raso, Daniel W Sazer, Don L Gibbons, William K Russell, Gregory D Longmore, Ignacio I Wistuba, Jing Wang, Harold A Chapman, Jordan S Miller, Chenghang Zong, Jonathan M Kurie.

  Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues from LUAD cells to promote metastasis.

Keywords:  EMT; cancer-associated fibroblast; invasion; lung cancer; metastasis; microRNA; secretion; single-cell RNA sequencing; tumor microenvironment

DOI:  https://doi.org/10.1016/j.celrep.2021.109009
Acta Biomater. 2021 Apr 17. pii: S1742-7061(21)00254-3. [Epub ahead of print]

Tissue-specific parameters for the design of ECM-mimetic biomaterials.

Olivia R Tonti, Hannah Larson, Sarah N Lipp, Callan M Luetkemeyer, Megan Makam, Diego Vargas, Sean M Wilcox, Sarah Calve.

  The extracellular matrix (ECM) is a complex network of biomolecules that mechanically and biochemically directs cell behavior and is crucial for maintaining tissue function and health. The heterogeneous organization and composition of the ECM varies within and between tissue types, directing mechanics, aiding in cell-cell communication, and facilitating tissue assembly and reassembly during development, injury and disease. As technologies like 3D printing rapidly advance, researchers are better able to recapitulate in vivo tissue properties in vitro; however, tissue-specific variations in ECM composition and organization are not given enough consideration. This is in part due to a lack of information regarding how the ECM of many tissues varies in both homeostatic and diseased states. To address this gap, we describe the components and organization of the ECM, and provide examples for different tissues at various states of disease. While many aspects of ECM biology remain unknown, our goal is to highlight the complexity of various tissues and inspire engineers to incorporate unique components of the native ECM into in vitro platform design and fabrication. Ultimately, we anticipate that the use of biomaterials that incorporate key tissue-specific ECM will lead to in vitro models that better emulate human pathologies. STATEMENT OF SIGNIFICANCE: Biomaterial development primarily emphasizes the engineering of new materials and therapies at the expense of identifying key parameters of the tissue that is being emulated. This can be partially attributed to the difficulty in defining the 3D composition, organization, and mechanics of the ECM within different tissues and how these material properties vary as a function of homeostasis and disease. In this review, we highlight a range of tissues throughout the body and describe how ECM content, cell diversity, and mechanical properties change in diseased tissues and influence cellular behavior. Accurately mimicking the tissue of interest in vitro by using ECM specific to the appropriate state of homeostasis or pathology in vivo will yield results more translatable to humans.

Keywords:  3D scaffolds; Biomechanics; Cell-cell communication; Extracellular matrix; Personalized medicine; in vitro cell culture

DOI:  https://doi.org/10.1016/j.actbio.2021.04.017
ACS Appl Mater Interfaces. 2021 Apr 20.

On-Chip Replication of Extremely Early-Stage Tumor Behavior.

Chengpan Li, Shibo Li, Kun Du, Ping Li, Bensheng Qiu, Weiping Ding.

  Cancer is a multistep progressive disease that generally involves tumor growth, invasion, and metastasis. It is crucial to understand tumor progression for tumor diagnosis and therapy. However, tumor progression at an extremely early stage (EES) is barely demonstrated because EES tumors are too small to be detected by imaging. Herein, we, for the first time, replicated tumor progression at the EES on a microfluidic chip and uncovered the tumor behaviors affected by the tumor microenvironment. To mimic the progression of a single solid tumor at the EES, a HeLa cell spheroid was seeded and cultured on the chip, and a microvascular network was developed to integrate the microphysiological contexts around the tumor. We revealed not only the growth patterns and cell behaviors of tumor spheroids of different sizes under angiogenesis and fibroblast conditions but also the effect of tumor progression on peritumoral angiogenesis. We found that smaller tumors were more aggressive and that endotheliocytes and fibroblasts significantly accelerated both the proliferation and migration of tumor cells. In addition, we also first present the dynamic epithelial-mesenchymal transition process of tumor cells and the formation of vasculogenic mimicry at the EES. This work can provide insights for understanding tumor progression at the EES and offer new ideas for tumor therapy.

Keywords:  angiogenesis; epithelial−mesenchymal transition; extremely early-stage tumor; microfluidic chip; vasculogenic mimicry

DOI:  https://doi.org/10.1021/acsami.1c03740
Clin Transl Oncol. 2021 Apr 19.

Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel.

L Sams, S Kruger, V Heinemann, D Bararia, S Haebe, S Alig, M Haas, D Zhang, C B Westphalen, S Ormanns, P Metzger, J Werner, O Weigert, M von Bergwelt-Baildon, F Rataj, S Kobold, S Boeck.

   PURPOSE: This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC).
PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome.
RESULTS: Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively.
CONCLUSIONS: Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

Keywords:  FOLFIRINOX; Gemcitabine; Immune checkpoints; Nab-paclitaxel; Pancreatic cancer; Regulatory T cells

DOI:  https://doi.org/10.1007/s12094-021-02620-x
Sci Adv. 2021 Apr;pii: eabf2400. [Epub ahead of print]7(17):

Immune cell shuttle for precise delivery of nanotherapeutics for heart disease and cancer.

San-Shan Huang, Keng-Jung Lee, Hung-Chih Chen, Ray Putra Prajnamitra, Chia-Hsin Hsu, Cheng-Bang Jian, Xu-En Yu, Di-Yen Chueh, Chiung Wen Kuo, Tsai-Chen Chiang, Oi Kuan Choong, Shao-Chan Huang, Chaw Yee Beh, Li-Lun Chen, James J Lai, Peilin Chen, Timothy J Kamp, Yu-Wen Tien, Hsien-Ming Lee, Patrick Ching-Ho Hsieh.

The delivery of therapeutics through the circulatory system is one of the least arduous and less invasive interventions; however, this approach is hampered by low vascular density or permeability. In this study, by exploiting the ability of monocytes to actively penetrate into diseased sites, we designed aptamer-based lipid nanovectors that actively bind onto the surface of monocytes and are released upon reaching the diseased sites. Our method was thoroughly assessed through treating two of the top causes of death in the world, cardiac ischemia-reperfusion injury and pancreatic ductal adenocarcinoma with or without liver metastasis, and showed a significant increase in survival and healing with no toxicity to the liver and kidneys in either case, indicating the success and ubiquity of our platform. We believe that this system provides a new therapeutic method, which can potentially be adapted to treat a myriad of diseases that involve monocyte recruitment in their pathophysiology.

DOI: https://doi.org/10.1126/sciadv.abf2400
Signal Transduct Target Ther. 2021 Apr 23. 6(1): 153

Extracellular matrix and its therapeutic potential for cancer treatment.

Jiacheng Huang, Lele Zhang, Dalong Wan, Lin Zhou, Shusen Zheng, Shengzhang Lin, Yiting Qiao.

The extracellular matrix (ECM) is one of the major components of tumors that plays multiple crucial roles, including mechanical support, modulation of the microenvironment, and a source of signaling molecules. The quantity and cross-linking status of ECM components are major factors determining tissue stiffness. During tumorigenesis, the interplay between cancer cells and the tumor microenvironment (TME) often results in the stiffness of the ECM, leading to aberrant mechanotransduction and further malignant transformation. Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment. Herein, we summarized the knowledge concerning the following: (1) major ECM constituents and their functions in both normal and malignant conditions; (2) the interplay between cancer cells and the ECM in the TME; (3) key receptors for mechanotransduction and their alteration during carcinogenesis; and (4) the current therapeutic strategies targeting aberrant ECM for cancer treatment.

DOI: https://doi.org/10.1038/s41392-021-00544-0