bims-tuchim 2021-08-29 papers

bims-tuchim

Biomed News

on Tumor-on-chip models

Issue of 2021–08–29
ten papers selected by
Philipp Albrecht, Friedrich Schiller University

Neutrophil in the Pancreatic Tumor Microenvironment.
A Personalized Glomerulus Chip Engineered from Stem Cell-Derived Epithelium and Vascular Endothelium.
Tissue Architecture Influences the Biological Effectiveness of Boron Neutron Capture Therapy in In Vitro/In Silico Three-Dimensional Self-Assembly Cell Models of Pancreatic Cancers.
Three-Dimensional Vascularized Lung Cancer-on-a-Chip with Lung Extracellular Matrix Hydrogels for In Vitro Screening.
Tumour-on-chip microfluidic platform for assessment of drug pharmacokinetics and treatment response.
Technological Advances in Tumor-On-Chip Technology: From Bench to Bedside.
Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer.
Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape.
Monocyte Infiltration and Differentiation in 3D Multicellular Spheroid Cancer Models.
Gain-of-function p53R172H mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy.

Biomolecules. 2021 Aug 07. pii: 1170. [Epub ahead of print]11(8):

Neutrophil in the Pancreatic Tumor Microenvironment.

Lin Jin, Hong Sun Kim, Jiaqi Shi.

  Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a poor prognosis and low survival rates. PDAC is characterized by a fibroinflammatory tumor microenvironment enriched by abundant fibroblasts and a variety of immune cells, contributing to its aggressiveness. Neutrophils are essential infiltrating immune cells in the PDAC microenvironment. Recent studies have identified several cellular mechanisms by which neutrophils are recruited to tumor lesion and promote tumorigenesis. This review summarizes the current understanding of the interplay between neutrophils, tumor cells, and other components in the PDAC tumor microenvironment. The prognosis and therapeutic implications of neutrophils in PDAC are also discussed.

Keywords:  immune cells; neutrophil extracellular traps; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3390/biom11081170
Micromachines (Basel). 2021 Aug 16. pii: 967. [Epub ahead of print]12(8):

A Personalized Glomerulus Chip Engineered from Stem Cell-Derived Epithelium and Vascular Endothelium.

Yasmin Roye, Rohan Bhattacharya, Xingrui Mou, Yuhao Zhou, Morgan A Burt, Samira Musah.

  Progress in understanding kidney disease mechanisms and the development of targeted therapeutics have been limited by the lack of functional in vitro models that can closely recapitulate human physiological responses. Organ Chip (or organ-on-a-chip) microfluidic devices provide unique opportunities to overcome some of these challenges given their ability to model the structure and function of tissues and organs in vitro. Previously established organ chip models typically consist of heterogenous cell populations sourced from multiple donors, limiting their applications in patient-specific disease modeling and personalized medicine. In this study, we engineered a personalized glomerulus chip system reconstituted from human induced pluripotent stem (iPS) cell-derived vascular endothelial cells (ECs) and podocytes from a single patient. Our stem cell-derived kidney glomerulus chip successfully mimics the structure and some essential functions of the glomerular filtration barrier. We further modeled glomerular injury in our tissue chips by administering a clinically relevant dose of the chemotherapy drug Adriamycin. The drug disrupts the structural integrity of the endothelium and the podocyte tissue layers, leading to significant albuminuria as observed in patients with glomerulopathies. We anticipate that the personalized glomerulus chip model established in this report could help advance future studies of kidney disease mechanisms and the discovery of personalized therapies. Given the remarkable ability of human iPS cells to differentiate into almost any cell type, this work also provides a blueprint for the establishment of more personalized organ chip and 'body-on-a-chip' models in the future.

Keywords:  disease models; endothelial cells; glomerulus chip; human induced pluripotent stem cells; kidney glomerulus; microfluidics; organ-on-a-chip; personalized medicine; podocytes; stem cell technologies

DOI:  https://doi.org/10.3390/mi12080967
Cancers (Basel). 2021 Aug 12. pii: 4058. [Epub ahead of print]13(16):

Tissue Architecture Influences the Biological Effectiveness of Boron Neutron Capture Therapy in In Vitro/In Silico Three-Dimensional Self-Assembly Cell Models of Pancreatic Cancers.

Lin-Sheng Yu, Megha Jhunjhunwala, Shiao-Ya Hong, Lin-Yen Yu, Wey-Ran Lin, Chi-Shuo Chen.

  Pancreatic cancer is a leading cause of cancer death, and boron neutron capture therapy (BNCT) is one of the promising radiotherapy techniques for patients with pancreatic cancer. In this study, we evaluated the biological effectiveness of BNCT at multicellular levels using in vitro and in silico models. To recapture the phenotypic characteristic of pancreatic tumors, we developed a cell self-assembly approach with human pancreatic cancer cells Panc-1 and BxPC-3 cocultured with MRC-5 fibroblasts. On substrate with physiological stiffness, tumor cells self-assembled into 3D spheroids, and the cocultured fibroblasts further facilitated the assembly process, which recapture the influence of tumor stroma. Interestingly, after 1.2 MW neutron irradiation, lower survival rates and higher apoptosis (increasing by 4-fold for Panc-1 and 1.5-fold for BxPC-3) were observed in 3D spheroids, instead of in 2D monolayers. The unexpected low tolerance of 3D spheroids to BNCT highlights the unique characteristics of BNCT over conventional radiotherapy. The uptake of boron-containing compound boronophenylalanine (BPA) and the alteration of E-cadherin can partially contribute to the observed susceptibility. In addition to biological effects, the probability of induced α-particle exposure correlated to the multicellular organization was speculated to affect the cellular responses to BNCT. A Monte Carlo (MC) simulation was also established to further interpret the observed survival. Intracellular boron distribution in the multicellular structure and related treatment resistance were reconstructed in silico. Simulation results demonstrated that the physical architecture is one of the essential factors for biological effectiveness in BNCT, which supports our in vitro findings. In summary, we developed in vitro and in silico self-assembly 3D models to evaluate the effectiveness of BNCT on pancreatic tumors. Considering the easy-access of this 3D cell-assembly platform, this study may not only contribute to the current understanding of BNCT but is also expected to be applied to evaluate the BNCT efficacy for individualized treatment plans in the future.

Keywords:  3D tumoroid; BNCT; cellular potts model; in silico simulation; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13164058
Cancers (Basel). 2021 Aug 05. pii: 3930. [Epub ahead of print]13(16):

Three-Dimensional Vascularized Lung Cancer-on-a-Chip with Lung Extracellular Matrix Hydrogels for In Vitro Screening.

Sangun Park, Tae Hee Kim, Soo Hyun Kim, Seungkwon You, Youngmee Jung.

  Recent advances in immunotherapies and molecularly targeted therapies have led to an increased interest in exploring the field of in vitro tumor mimetic platforms. An increasing need to understand the mechanisms of anti-cancer therapies has led to the development of natural tumor tissue-like in vitro platforms capable of simulating the tumor microenvironment. The incorporation of vascular structures into the in vitro platforms could be a crucial factor for functional investigation of most anti-cancer therapies, including immunotherapies, which are closely related to the circulatory system. Decellularized lung extracellular matrix (ldECM), comprised of ECM components and pro-angiogenic factors, can initiate vascularization and is ideal for mimicking the natural microenvironment. In this study, we used a ldECM-based hydrogel to develop a 3D vascularized lung cancer-on-a-chip (VLCC). We specifically encapsulated tri-cellular spheroids made from A549 cells, HUVECs, and human lung fibroblasts, for simulating solid type lung cancer. Additionally, two channels were incorporated in the hydrogel construct to mimic perfusable vessel structures that resemble arterioles or venules. Our study highlights how a more effective dose-dependent action of the anti-cancer drug Doxorubicin was observed using a VLCC over 2D screening. This observation confirmed the potential of the VLCC as a 3D in vitro drug screening tool.

Keywords:  angiogenesis; cancer-on-a-chip; decellularized extracellular matrix; drug screening; tumor microenvironment; vascularization

DOI:  https://doi.org/10.3390/cancers13163930
Commun Biol. 2021 Aug 24. 4(1): 1001

Tumour-on-chip microfluidic platform for assessment of drug pharmacokinetics and treatment response.

Tudor Petreus, Elaine Cadogan, Gareth Hughes, Aaron Smith, Venkatesh Pilla Reddy, Alan Lau, Mark James O'Connor, Susan Critchlow, Marianne Ashford, Lenka Oplustil O'Connor.

Microphysiological in vitro systems are platforms for preclinical evaluation of drug effects and significant advances have been made in recent years. However, existing microfluidic devices are not yet able to deliver compounds to cell models in a way that reproduces the real physiological drug exposure. Here, we introduce a novel tumour-on-chip microfluidic system that mimics the pharmacokinetic profile of compounds on 3D tumour spheroids to evaluate their response to the treatments. We used this platform to test the response of SW620 colorectal cancer spheroids to irinotecan (SN38) alone and in combination with the ATM inhibitor AZD0156, using concentrations mimicking mouse plasma exposure profiles of both agents. We explored spheroid volume and viability as a measure of cancer cells response and changes in mechanistically relevant pharmacodynamic biomarkers (γH2AX, cleaved-caspase 3 and Ki67). We demonstrate here that our microfluidic tumour-on-chip platform can successfully predict the efficacy from in vivo studies and therefore represents an innovative tool to guide drug dose and schedules for optimal efficacy and pharmacodynamic assessment, while reducing the need for animal studies.

DOI: https://doi.org/10.1038/s42003-021-02526-y
Cancers (Basel). 2021 Aug 20. pii: 4192. [Epub ahead of print]13(16):

Technological Advances in Tumor-On-Chip Technology: From Bench to Bedside.

Santa Bērziņa, Alexandra Harrison, Valérie Taly, Wenjin Xiao.

  Tumor-on-chip technology has cemented its importance as an in vitro tumor model for cancer research. Its ability to recapitulate different elements of the in vivo tumor microenvironment makes it promising for translational medicine, with potential application in enabling personalized anti-cancer therapies. Here, we provide an overview of the current technological advances for tumor-on-chip generation. To further elevate the functionalities of the technology, these approaches need to be coupled with effective analysis tools. This aspect of tumor-on-chip technology is often neglected in the current literature. We address this shortcoming by reviewing state-of-the-art on-chip analysis tools for microfluidic tumor models. Lastly, we focus on the current progress in tumor-on-chip devices using patient-derived samples and evaluate their potential for clinical research and personalized medicine applications.

Keywords:  cancer research; on-chip analysis; personalized medicine; tumor model; tumor-on-chip

DOI:  https://doi.org/10.3390/cancers13164192
Cancers (Basel). 2021 Aug 23. pii: 4235. [Epub ahead of print]13(16):

Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer.

Anna Maxi Wandmacher, Anne Letsch, Susanne Sebens.

  To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC's characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a "one-fits-all" immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC.

Keywords:  PDAC; cancer vaccine; checkpoint inhibition; immunosuppression; translational research; tumour microenvironment

DOI:  https://doi.org/10.3390/cancers13164235
Nat Commun. 2021 Aug 26. 12(1): 5151

Tumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape.

Kristin C Hicks, Paul L Chariou, Yohei Ozawa, Christine M Minnar, Karin M Knudson, Thomas J Meyer, Jing Bian, Margaret Cam, Jeffrey Schlom, Sofia R Gameiro.

Poorly inflamed carcinomas do not respond well to immune checkpoint blockade. Converting the tumour microenvironment into a functionally inflamed immune hub would extend the clinical benefit of immune therapy to a larger proportion of cancer patients. Here we show, by using comprehensive single-cell transcriptome, proteome, and immune cell analysis, that Entinostat, a class I histone deacetylase inhibitor, facilitates accumulation of the necrosis-targeted recombinant murine immune-cytokine, NHS-rmIL12, in experimental mouse colon carcinomas and poorly immunogenic breast tumours. This combination therapy reprograms the tumour innate and adaptive immune milieu to an inflamed landscape, where the concerted action of highly functional CD8+ T cells and activated neutrophils drive macrophage M1-like polarization, leading to complete tumour eradication in 41.7%-100% of cases. Biomarker signature of favourable overall survival in multiple human tumor types shows close resemblance to the immune pattern generated by Entinostat/NHS-rmIL12 combination therapy. Collectively, these findings provide a rationale for combining NHS-IL12 with Entinostat in the clinical setting.

DOI: https://doi.org/10.1038/s41467-021-25393-x
Pathogens. 2021 Jul 30. pii: 969. [Epub ahead of print]10(8):

Monocyte Infiltration and Differentiation in 3D Multicellular Spheroid Cancer Models.

Natasha Helleberg Madsen, Boye Schnack Nielsen, Son Ly Nhat, Søren Skov, Monika Gad, Jesper Larsen.

  Tumor-associated macrophages often correlate with tumor progression, and therapies targeting immune cells in tumors have emerged as promising treatments. To select effective therapies, we established an in vitro 3D multicellular spheroid model including cancer cells, fibroblasts, and monocytes. We analyzed monocyte infiltration and differentiation in spheroids generated from fibroblasts and either of the cancer cell lines MCF-7, HT-29, PANC-1, or MIA PaCa-2. Monocytes rapidly infiltrated spheroids and differentiated into mature macrophages with diverse phenotypes in a cancer cell line-dependent manner. MIA PaCa-2 spheroids polarized infiltrating monocytes to M2-like macrophages with high CD206 and CD14 expression, whereas monocytes polarized by MCF-7 spheroids displayed an M1-like phenotype. Monocytes in HT-29 and PANC-1 primarily obtained an M2-like phenotype but also showed upregulation of M1 markers. Analysis of the secretion of 43 soluble factors demonstrated that the cytokine profile between spheroid cultures differed considerably depending on the cancer cell line. Secretion of most of the cytokines increased upon the addition of monocytes resulting in a more inflammatory and pro-tumorigenic environment. These multicellular spheroids can be used to recapitulate the tumor microenvironment and the phenotype of tumor-associated macrophages in vitro and provide more realistic 3D cancer models allowing the in vitro screening of immunotherapeutic compounds.

Keywords:  3D cancer cell models; drug screening; in vitro assay; multicellular spheroids; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/pathogens10080969
Cell Rep. 2021 Aug 24. pii: S2211-1247(21)01012-3. [Epub ahead of print]36(8): 109578

Gain-of-function p53R172H mutation drives accumulation of neutrophils in pancreatic tumors, promoting resistance to immunotherapy.

Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi.

  Tumor genotype can influence the immune microenvironment, which plays a critical role in cancer development and therapy resistance. However, the immune effects of gain-of-function Trp53 mutations have not been defined in pancreatic cancer. We compare the immune profiles generated by KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDECs) engineered genetically to express the Trp53R172H mutation with their p53 wild-type control. KrasG12D/+;Trp53R172H/+ tumors have a distinct immune profile characterized by an influx of CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 cells. Knockdown of CXCL2, a neutrophil chemokine, in the tumor epithelial compartment of CRISPR KrasG12D/+;Trp53R172H/+ PDEC tumors reverses the neutrophil phenotype. Neutrophil depletion of mice bearing CRISPR KrasG12D/+;Trp53R172H/+ tumors augments sensitivity to combined CD40 immunotherapy and chemotherapy. These data link Trp53R172H to the presence of intratumoral neutrophils in pancreatic cancer and suggest that tumor genotypes could inform selection of affected individuals for immunotherapy.

Keywords:  immune microenvironment; mutant p53; neutrophils; pancreatic cancer

DOI:  https://doi.org/10.1016/j.celrep.2021.109578