Background The majority of patients with pancreatic cancer develops cachexia. The mechanisms underlying cancer cachexia development and progression remain elusive, although tumour-derived factors are considered to play a major role. Pancreatic tumour organoids are in vitro three-dimensional organ-like structures that retain many pathophysiological characteristics of the in vivo tumour. We aimed to establish a pancreatic tumour organoid biobank from well-phenotyped cachectic and non-cachectic patients to enable identification of tumour-derived factors driving cancer cachexia. Methods Organoids were generated from tumour tissue of eight pancreatic cancer patients. A comprehensive pre-operative patient assessment of cachexia-related parameters including nutritional status, physical performance, body composition, and inflammation was performed. Tumour-related and cachexia-related characteristics of the organoids were analysed using histological stainings, targeted sequencing, and real-time-quantitative PCR. Cachexia-related factors present in the circulation of the patients and in the tumour organoid secretome were analysed by enzyme-linked immunosorbent assay. Results The established human pancreatic tumour organoids presented typical features of malignancy corresponding to the primary tumour (i.e. nuclear enlargement, multiple nucleoli, mitosis, apoptosis, and mutated KRAS and/or TP53). These tumour organoids also expressed variable levels of many known cachexia-related genes including interleukin-6 (IL-6), TNF-α, IL-8, IL-1α, IL-1β, Mcp-1, GDF15, and LIF. mRNA expression of IL-1α and IL-1β was significantly reduced in organoids from cachectic vs. non-cachectic patients (IL-1α: À3.8-fold, P = 0.009, and IL-1β: À4.7-fold, P = 0.004). LIF, IL-8, and GDF15 mRNA expression levels were significantly higher in organoids from cachectic vs. non-cachectic patients (LIF: 1.6-fold, P = 0.003; IL-8: 1.4-fold, P = 0.01; GDF15: 2.3-fold, P < 0.001). In line with the GDF15 and IL-8 mRNA expression levels, tumour organoids from cachectic patients secreted more GDF15 and IL-8 compared with organoids from non-cachectic patients (5.4 vs. 1.5 ng/mL, P = 0.01, and 7.4 vs. 1.3 ng/mL, P = 0.07, respectively). Conclusions This novel human pancreatic tumour organoid biobank provides a valuable tool to increase our understanding of the mechanisms driving cancer cachexia. Our preliminary characterization of the secretome of these organoids supports their application in functional studies including conditioned medium approaches and in vivo transplantation models.

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal.If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the "Taverne" license above, please follow below link for the End User