A biomimetic pancreatic cancer on-chip reveals endothelial ablation via ALK7 signaling

Nguyen, Duc-Huy T.; Lee, Esak; Alimperti, Styliani; Norgard, Robert J.; Wong, Alec; Lee, Jake June-Koo; Eyckmans, Jeroen; Stanger, Ben Z.; Chen, Christopher

doi:10.1126/sciadv.aav6789

Cited by 129 publications

(123 citation statements)

References 40 publications

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“…More recently, this method was deployed to reveal pathological interactions between pancreatic cancer cells and endothelial cells. 20 The integrative nexus of cancer, vascular biology, and hematology has not been modeled thus far. We have designed a tumor-vessel-blood-integrated organ chip (the OvCa-Chip) that provides insight into the time-dependent endothelial activity that occurs near ovarian cancer tissue and, consequently, its contribution to platelet extravasation from the bloodstream into the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

OvCa-Chip microsystem recreates vascular endothelium–mediated platelet extravasation in ovarian cancer

Saha

Mathur

Handley³

et al. 2020

Blood Advances

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In ovarian cancer, platelet extravasation into the tumor and resulting metastasis is thought to be regulated mostly by the vascular endothelium. Because it is difficult to dissect complex underlying events in murine models, organ-on-a-chip methodology is applied to model vascular and platelet functions in ovarian cancer. This system (OvCa-Chip) consists of microfluidic chambers that are lined by human ovarian tumor cells interfaced with a 3-dimensional endothelialized lumen. Subsequent perfusion with human platelets within the device’s vascular endothelial compartment under microvascular shear conditions for 5 days uncovered organ-to-molecular–level contributions of the endothelium to triggering platelet extravasation into tumors. Further, analysis of effluents available from the device’s individual tumor and endothelial chambers revealed temporal dynamics of vascular disintegration caused by cancer cells, a differential increase in cytokine expression, and an alteration of barrier maintenance genes in endothelial cells. These events, when analyzed within the device over time, made the vascular tissue leaky and promoted platelet extravasation. Atorvastatin treatment of the endothelial cells within the OvCa-Chip revealed improved endothelial barrier function, reduction in inflammatory cytokines and, eventually, arrest of platelet extravasation. These data were validated through corresponding observations in patient-derived tumor samples. The OvCa-Chip provides a novel in vitro dissectible platform to model the mechanisms of the cancer-vascular-hematology nexus and the analyses of potential therapeutics.

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Section: Introductionmentioning

confidence: 99%

OvCa-Chip microsystem recreates vascular endothelium–mediated platelet extravasation in ovarian cancer

Saha

Mathur

Handley³

et al. 2020

Blood Advances

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“…This will create a 3D cylindrical system which is more physiologically relevant to the tubular structures of the blood and lymphatic vessels (see Figure 5b). A 3D organotypic model of tubular blood vessels was previously created to study the interactions with the pancreatic cancer cells and the blood vessels [130]. The same method can be further applied to create biomimetic lymphatic vessels.…”

Section: Intestinal-vasculature-on-a-chipmentioning

confidence: 99%

Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling

2020

Self Cite

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The human circulatory system is divided into two complementary and different systems, the cardiovascular and the lymphatic system. The cardiovascular system is mainly concerned with providing nutrients to the body via blood and transporting wastes away from the tissues to be released from the body. The lymphatic system focuses on the transport of fluid, cells, and lipid from interstitial tissue spaces to lymph nodes and, ultimately, to the cardiovascular system, as well as helps coordinate interstitial fluid and lipid homeostasis and immune responses. In addition to having distinct structures from each other, each system also has organ-specific variations throughout the body and both systems play important roles in maintaining homeostasis. Dysfunction of either system leads to devastating and potentially fatal diseases, warranting accurate models of both blood and lymphatic vessels for better studies. As these models also require physiological flow (luminal and interstitial), extracellular matrix conditions, dimensionality, chemotactic biochemical gradient, and stiffness, to better reflect in vivo, three dimensional (3D) microfluidic (on-a-chip) devices are promising platforms to model human physiology and pathology. In this review, we discuss the heterogeneity of both blood and lymphatic vessels, as well as current in vitro models. We, then, explore the organ-specific features of each system with examples in the gut and the brain and the implications of dysfunction of either vasculature in these organs. We close the review with discussions on current in vitro models for specific diseases with an emphasis on on-chip techniques.

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“…The precise control and orientation of cells within scaffolds in 3D tissue chips also allows for more physiologically relevant studies of cellular migration. For example, a polymeric silicone microfluidic device with parallel hollow lumens embedded in collagen helped to elucidate the signaling pathways that promote pancreatic cancer metastases [ 235 ]. Specifically, the model helped to show that adenocarcinoma metastases relied on pancreatic ductal endothelial ablation that was dependent on the ALK7 pathway of TGF-β signaling and that broad-spectrum inhibitors of TGF -β signaling could limit this effect [ 235 ].…”

Section: Engineering Advances: Assembling Advanced In Vitromentioning

confidence: 99%

Engineered tissues and strategies to overcome challenges in drug development

Khalil

Jaenisch

Mooney

2020

Advanced Drug Delivery Reviews

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Current preclinical studies in drug development utilize high-throughput in vitro screens to identify lead drug candidates, followed by both in vitro and in vivo models to predict lead candidates' pharmacokinetic and pharmacodynamic properties. The goal of these studies is to reduce the number of lead drug candidates down to the most likely to succeed in later human clinical trials. However, only 1 in 10 drug candidates that emerge from preclinical studies will succeed and become an approved therapeutic. Lack of efficacy or undetected toxicity represents roughly 75% of the causes for these failures, despite these parameters being the primary exclusion criteria in preclinical studies. Recently, advances in both biology and engineering have created new tools for constructing new preclinical models. These models can complement those used in current preclinical studies by helping to create more realistic representations of human tissues in vitro and in vivo . In this review, we describe current preclinical models to identify their value and limitations and then discuss select areas of research where improvements in preclinical models are particularly needed to advance drug development. Following this, we discuss design considerations for constructing preclinical models and then highlight recent advances in these efforts. Taken together, we aim to review the advances as of 2020 surrounding the prospect of biological and engineering tools for adding enhanced biological relevance to preclinical studies to aid in the challenges of failed drug candidates and the burden this poses on the drug development enterprise and thus healthcare.

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A biomimetic pancreatic cancer on-chip reveals endothelial ablation via ALK7 signaling

Cited by 129 publications

References 40 publications

OvCa-Chip microsystem recreates vascular endothelium–mediated platelet extravasation in ovarian cancer

OvCa-Chip microsystem recreates vascular endothelium–mediated platelet extravasation in ovarian cancer

Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling

Engineered tissues and strategies to overcome challenges in drug development

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