bims-tuchim 2021-10-10 papers

J Cell Sci. 2021 Oct 08. pii: jcs.258690. [Epub ahead of print]

Transendothelial migration induces differential migration dynamics of leukocytes in tissue matrix.

Abraham C I van Steen, Lanette Kempers, Rouven Schoppmeyer, Max Blokker, David J Beebe, Martijn A Nolte, Jaap D van Buul.

Leukocyte extravasation into inflamed tissue is a complex process that is difficult to capture as a whole in vitro. We employed a blood-vessel-on-a-chip model in which endothelial cells were cultured in a tube-like lumen in a collagen-1 matrix. The vessels are leak-tight, creating a barrier for molecules and leukocytes. Addition of inflammatory cytokine TNF-α caused vasoconstriction, actin remodelling and upregulation of ICAM-1. Introducing leukocytes into the vessels allowed real-time visualisation of all different steps of the leukocyte transmigration cascade including migration into the extracellular matrix. Individual cell tracking over time distinguished striking differences in migratory behaviour between T-cells and neutrophils. Neutrophils cross the endothelial layer more efficiently than T-cells, but upon entering the matrix, neutrophils display high speed but low persistence, whereas T-cells migrate with low speed and rather linear migration. In conclusion, 3D imaging in real-time of leukocyte extravasation in a vessel-on-a-chip enables detailed qualitative and quantitative analysis of different stages of the full leukocyte extravasation process in a single assay.

Keywords: Blood vessels; Blood-vessel-on-a-chip; Endothelial cells; Extracellular matrix; Inflammation; Leukocyte transendothelial migration; Migration dynamics.; Physiological hydrogel; Tissue

DOI: https://doi.org/10.1242/jcs.258690

Mol Cancer Ther. 2021 Oct 08. pii: molcanther.0368.2021. [Epub ahead of print]

IgE-based therapeutic combination enhances anti-tumor response in preclinical models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents 3% of all cancer cases and 7% of all cancer deaths in the United States. Late diagnosis and inadequate response to standard chemotherapies contribute to an unfavorable prognosis and an overall 5-year survival rate of less than 10% in PDAC. Despite recent advances in tumor immunology, tumor-induced immunosuppression attenuates the immunotherapy response in PDAC. To date, studies have focused on IgG-based therapeutic strategies in PDAC. With the recent interest in IgE-based therapies in multiple solid tumors, we explored the MUC1-targeted IgE antibody's potential against pancreatic cancer. Our study demonstrates the notable expression of FcεRI (receptor for IgE antibody) in PDAC patients. Our study showed that administration with a limited amount of MUC1 targeted-IgE (mouse/human chimeric anti-MUC1.IgE) antibody at intermittent levels in combination with checkpoint inhibitor (anti-PD-L1) and TLR3 agonist (PolyICLC) induces a robust anti-tumor response that is dependent on NK and CD8 T cells in pancreatic tumor-bearing mice. Subsequently, our study showed that IgE antibody's antigen specificity plays a vital role in executing the anti-tumor response as non-specific IgE, induced by ovalbumin (OVA), failed to restrict tumor growth in pancreatic tumor-bearing mice. Utilizing the OVA-induced allergic asthma-PDAC model, we demonstrate that allergic phenotype induced by OVA cannot restrain pancreatic tumor growth in orthotopic tumor-bearing mice. Together, our data demonstrate the novel tumor protective benefits of tumor antigen-specific IgE-based therapeutics in a preclinical model of pancreatic cancer, which can open new avenues for future clinical interventions.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0368

Nat Commun. 2021 Oct 05. 12(1): 5826

Single-cell analysis of patient-derived PDAC organoids reveals cell state heterogeneity and a conserved developmental hierarchy.

Teresa G Krieger, Solange Le Blanc, Julia Jabs, Foo Wei Ten, Naveed Ishaque, Katharina Jechow, Olivia Debnath, Carl-Stephan Leonhardt, Anamika Giri, Roland Eils, Oliver Strobel, Christian Conrad.

Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer mortality by 2030. Bulk transcriptomic analyses have distinguished 'classical' from 'basal-like' tumors with more aggressive clinical behavior. We derive PDAC organoids from 18 primary tumors and two matched liver metastases, and show that 'classical' and 'basal-like' cells coexist in individual organoids. By single-cell transcriptome analysis of PDAC organoids and primary PDAC, we identify distinct tumor cell states shared across patients, including a cycling progenitor cell state and a differentiated secretory state. Cell states are connected by a differentiation hierarchy, with 'classical' cells concentrated at the endpoint. In an imaging-based drug screen, expression of 'classical' subtype genes correlates with better drug response. Our results thus uncover a functional hierarchy of PDAC cell states linked to transcriptional tumor subtypes, and support the use of PDAC organoids as a clinically relevant model for in vitro studies of tumor heterogeneity.

DOI: https://doi.org/10.1038/s41467-021-26059-4