bims-tuchim 2021-10-31 papers

Biomater Sci. 2021 Oct 27.

A 3D pancreatic tumor model to study T cell infiltration.

Hilaria Mollica, Yi Juan Teo, Alrina Shin Min Tan, Damien Zhi Ming Tan, Paolo Decuzzi, Andrea Pavesi, Giulia Adriani.

The desmoplastic nature of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) prevents the infiltration of T cells and the penetration of chemotherapeutic drugs, posing a challenge to the validation of targeted therapies, including T cell immunotherapies. We present an in vitro 3D PDAC-TME model to observe and quantify T cell infiltration across the vasculature. In a three-channel microfluidic device, PDAC cells are cultured in a collagen matrix in the central channel surrounded, on one side, by endothelial cells (ECs) to mimic a blood vessel and, on the opposite side, by pancreatic stellate cells (PSCs) to simulate exocrine pancreas. The migration of T cells toward the tumor is quantified based on their activation state and TME composition. The presence of EC-lining drastically reduces T cell infiltration, confirming the essential role of the vasculature in controlling T cell trafficking. We show that activated T cells migrate ∼50% more than the not-activated ones toward the cancer cells. Correspondingly, in the absence of cancer cells, both activated and not-activated T cells present similar migration toward the PSCs. The proposed approach could help researchers in testing and optimizing immunotherapies for pancreatic cancer.

DOI: https://doi.org/10.1039/d1bm00210d

Front Digit Health. 2021 ;3 704584

3D Collagen-Nanocellulose Matrices Model the Tumour Microenvironment of Pancreatic Cancer.

Rodrigo Curvello, Verena Kast, Mohammed H Abuwarwar, Anne L Fletcher, Gil Garnier, Daniela Loessner.

Three-dimensional (3D) cancer models are invaluable tools designed to study tumour biology and new treatments. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of cancer, has been progressively explored with bioengineered 3D approaches by deconstructing elements of its tumour microenvironment. Here, we investigated the suitability of collagen-nanocellulose hydrogels to mimic the extracellular matrix of PDAC and to promote the formation of tumour spheroids and multicellular 3D cultures with stromal cells. Blending of type I collagen fibrils and cellulose nanofibres formed a matrix of controllable stiffness, which resembled the lower profile of pancreatic tumour tissues. Collagen-nanocellulose hydrogels supported the growth of tumour spheroids and multicellular 3D cultures, with increased metabolic activity and matrix stiffness. To validate our 3D cancer model, we tested the individual and combined effects of the anti-cancer compound triptolide and the chemotherapeutics gemcitabine and paclitaxel, resulting in differential cell responses. Our blended 3D matrices with tuneable mechanical properties consistently maintain the growth of PDAC cells and its cellular microenvironment and allow the screening of anti-cancer treatments.

Keywords: collagen; extracellular matrix; hydrogels; nanocellulose; pancreatic cancer; stiffness

DOI: https://doi.org/10.3389/fdgth.2021.704584

Front Physiol. 2021 ;12 735915

Classical and Non-classical Fibrosis Phenotypes Are Revealed by Lung and Cardiac Like Microvascular Tissues On-Chip.

Akinola Akinbote, Violeta Beltran-Sastre, Marta Cherubini, Roberta Visone, Cynthia Hajal, Defne Cobanoglu, Kristina Haase.

Fibrosis, a hallmark of many cardiac and pulmonary diseases, is characterized by excess deposition of extracellular matrix proteins and increased tissue stiffness. This serious pathologic condition is thought to stem majorly from local stromal cell activation. Most studies have focused on the role of fibroblasts; however, the endothelium has been implicated in fibrosis through direct and indirect contributions. Here, we present a 3D vascular model to investigate vessel-stroma crosstalk in normal conditions and following induced fibrosis. Human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) are co-cultured with (and without) primary human cardiac and lung fibroblasts (LFs) in a microfluidic device to generate perfusable microvasculature in cardiac- and pulmonary-like microenvironments. Endothelial barrier function, vascular morphology, and matrix properties (stiffness and diffusivity) are differentially impacted by the presence of stromal cells. These vessels (with and without stromal cells) express inflammatory cytokines, which could induce a wound-healing state. Further treatment with transforming growth factor-β (TGF-β) induced varied fibrotic phenotypes on-chip, with LFs resulting in increased stiffness, lower MMP activity, and increased smooth muscle actin expression. Taken together, our work demonstrates the strong impact of stromal-endothelial interactions on vessel formation and extravascular matrix regulation. The role of TGF-β is shown to affect co-cultured microvessels differentially and has a severe negative impact on the endothelium without stromal cell support. Our human 3D in vitro model has the potential to examine anti-fibrotic therapies on patient-specific hiPSCs in the future.

Keywords: ECM remodeling; TGF-β; cardiac fibrosis; fibrosis on-chip; matrix metalloproteases; microfluidics; microvasculature; pulmonary fibrosis

DOI: https://doi.org/10.3389/fphys.2021.735915

Front Oncol. 2021 ;11 751311

The PDAC Extracellular Matrix: A Review of the ECM Protein Composition, Tumor Cell Interaction, and Therapeutic Strategies.

Vincent M Perez, Joseph F Kearney, Jen Jen Yeh.

Pancreatic ductal adenocarcinoma (PDAC) is notorious for a dense fibrotic stroma that is interlaced with a collagen-based extracellular matrix (ECM) that plays an important role in tumor biology. Traditionally thought to only provide a physical barrier from host responses and systemic chemotherapy, new studies have demonstrated that the ECM maintains biomechanical and biochemical properties of the tumor microenvironment (TME) and restrains tumor growth. Recent studies have shown that the ECM augments tumor stiffness, interstitial fluid pressure, cell-to-cell junctions, and microvascularity using a mix of biomechanical and biochemical signals to influence tumor fate for better or worse. In addition, PDAC tumors have been shown to use ECM-derived peptide fragments as a nutrient source in nutrient-poor conditions. While collagens are the most abundant proteins found in the ECM, several studies have identified growth factors, integrins, glycoproteins, and proteoglycans in the ECM. This review focuses on the dichotomous nature of the PDAC ECM, the types of collagens and other proteins found in the ECM, and therapeutic strategies targeting the PDAC ECM.

Keywords: cancer; extracellular matrix; pancreatic ductal adenocarcinoma; proteome; tumor microenvironment

DOI: https://doi.org/10.3389/fonc.2021.751311