bims-tuchim 2021-09-26 papers

Trends Biotechnol. 2021 Sep 20. pii: S0167-7799(21)00194-3. [Epub ahead of print]

3D-bioprinted cancer-on-a-chip: level-up organotypic in vitro models.

Maria V Monteiro, Yu Shrike Zhang, Vítor M Gaspar, João F Mano.

Combinatorial conjugation of organ-on-a-chip platforms with additive manufacturing technologies is rapidly emerging as a disruptive approach for upgrading cancer-on-a-chip systems towards anatomic-sized dynamic in vitro models. This valuable technological synergy has potential for giving rise to truly physiomimetic 3D models that better emulate tumor microenvironment elements, bioarchitecture, and response to multidimensional flow dynamics. Herein, we showcase the most recent advances in bioengineering 3D-bioprinted cancer-on-a-chip platforms and provide a comprehensive discussion on design guidelines and possibilities for high-throughput analysis. Such hybrid platforms represent a new generation of highly sophisticated 3D tumor models with improved biomimicry and predictability of therapeutics performance.

Keywords: 3D bioprinting; cancer-on-a-chip; in vitro tumor models; preclinical drug screening

DOI: https://doi.org/10.1016/j.tibtech.2021.08.007

Cancer Discov. 2021 Sep 21. pii: candisc.0601.2021. [Epub ahead of print]

Mesenchymal Lineage Heterogeneity Underlies Non-Redundant Functions of Pancreatic Cancer-Associated Fibroblasts.

Erin J Helms, Mark W Berry, R Crystal Chaw, Christopher C DuFort, Duanchen Sun, M Kathrina Onate, Chet Oon, Sohinee Bhattacharyya, Hannah Sanford-Crane, Wesley Horton, Jennifer M Finan, Ariana Sattler, Rosemary Makar, David W Dawson, Zheng Xia, Sunil R Hingorani, Mara H Sherman.

Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSCs), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed non-redundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs, and demonstrate unique functions for CAFs of a defined cellular origin.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0601

Front Pharmacol. 2021 ;12 707891

A Synthetic Hydrogel, VitroGel® ORGANOID-3, Improves Immune Cell-Epithelial Interactions in a Tissue Chip Co-Culture Model of Human Gastric Organoids and Dendritic Cells.

Michelle D Cherne, Barkan Sidar, T Andrew Sebrell, Humberto S Sanchez, Kody Heaton, Francis J Kassama, Mandi M Roe, Andrew B Gentry, Connie B Chang, Seth T Walk, Mark Jutila, James N Wilking, Diane Bimczok.

Immunosurveillance of the gastrointestinal epithelium by mononuclear phagocytes (MNPs) is essential for maintaining gut health. However, studying the complex interplay between the human gastrointestinal epithelium and MNPs such as dendritic cells (DCs) is difficult, since traditional cell culture systems lack complexity, and animal models may not adequately represent human tissues. Microphysiological systems, or tissue chips, are an attractive alternative for these investigations, because they model functional features of specific tissues or organs using microscale culture platforms that recreate physiological tissue microenvironments. However, successful integration of multiple of tissue types on a tissue chip platform to reproduce physiological cell-cell interactions remains a challenge. We previously developed a tissue chip system, the gut organoid flow chip (GOFlowChip), for long term culture of 3-D pluripotent stem cell-derived human intestinal organoids. Here, we optimized the GOFlowChip platform to build a complex microphysiological immune-cell-epithelial cell co-culture model in order to study DC-epithelial interactions in human stomach. We first tested different tubing materials and chip configurations to optimize DC loading onto the GOFlowChip and demonstrated that DC culture on the GOFlowChip for up to 20 h did not impact DC activation status or viability. However, Transwell chemotaxis assays and live confocal imaging revealed that Matrigel, the extracellular matrix (ECM) material commonly used for organoid culture, prevented DC migration towards the organoids and the establishment of direct MNP-epithelial contacts. Therefore, we next evaluated DC chemotaxis through alternative ECM materials including Matrigel-collagen mixtures and synthetic hydrogels. A polysaccharide-based synthetic hydrogel, VitroGel®-ORGANOID-3 (V-ORG-3), enabled significantly increased DC chemotaxis through the matrix, supported organoid survival and growth, and did not significantly alter DC activation or viability. On the GOFlowChip, DCs that were flowed into the chip migrated rapidly through the V-ORG matrix and reached organoids embedded deep within the chip, with increased interactions between DCs and gastric organoids. The successful integration of DCs and V-ORG-3 embedded gastric organoids into the GOFlowChip platform now permits real-time imaging of MNP-epithelial interactions and other investigations of the complex interplay between gastrointestinal MNPs and epithelial cells in their response to pathogens, candidate drugs and mucosal vaccines.

Keywords: chemotaxis; dendritic cell; gastric organoid; hydrogel; matrigel; microphysiological system; mononuclear phagocyte

DOI: https://doi.org/10.3389/fphar.2021.707891

Nat Commun. 2021 Sep 24. 12(1): 5623

Bioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology.

David Osuna de la Peña, Sara Maria David Trabulo, Estelle Collin, Ying Liu, Shreya Sharma, Marianthi Tatari, Diana Behrens, Mert Erkan, Rita T Lawlor, Aldo Scarpa, Christopher Heeschen, Alvaro Mata, Daniela Loessner.

Patient-derived in vivo models of human cancer have become a reality, yet their turnaround time is inadequate for clinical applications. Therefore, tailored ex vivo models that faithfully recapitulate in vivo tumour biology are urgently needed. These may especially benefit the management of pancreatic ductal adenocarcinoma (PDAC), where therapy failure has been ascribed to its high cancer stem cell (CSC) content and high density of stromal cells and extracellular matrix (ECM). To date, these features are only partially reproduced ex vivo using organoid and sphere cultures. We have now developed a more comprehensive and highly tuneable ex vivo model of PDAC based on the 3D co-assembly of peptide amphiphiles (PAs) with custom ECM components (PA-ECM). These cultures maintain patient-specific transcriptional profiles and exhibit CSC functionality, including strong in vivo tumourigenicity. User-defined modification of the system enables control over niche-dependent phenotypes such as epithelial-to-mesenchymal transition and matrix deposition. Indeed, proteomic analysis of these cultures reveals improved matrisome recapitulation compared to organoids. Most importantly, patient-specific in vivo drug responses are better reproduced in self-assembled cultures than in other models. These findings support the use of tuneable self-assembling platforms in cancer research and pave the way for future precision medicine approaches.

DOI: https://doi.org/10.1038/s41467-021-25921-9