Publications

Abstract Background Organoids are 3-dimensional experimental models that summarize the anatomical and functional structure of an organ. Although a promising experimental model for precision medicine, patient-derived tumor organoids (PDTOs) have currently been developed only for a fraction of tumor types. Results We have generated the first multi-omic dataset (whole-genome sequencing [WGS] and RNA-sequencing [RNA-seq]) of PDTOs from the rare and understudied pulmonary neuroendocrine tumors (n = 12; 6 grade 1, 6 grade 2) and provide data from other rare neuroendocrine neoplasms: small intestine (ileal) neuroendocrine tumors (n = 6; 2 grade 1 and 4 grade 2) and large-cell neuroendocrine carcinoma (n = 5; 1 pancreatic and 4 pulmonary). This dataset includes a matched sample from the parental sample (primary tumor or metastasis) for a majority of samples (21/23) and longitudinal sampling of the PDTOs (1 to 2 time points), for a total of n = 47 RNA-seq and n = 33 WGS. We here provide quality control for each technique and the raw and processed data as well as all scripts for genomic analyses to ensure an optimal reuse of the data. In addition, we report gene expression data and somatic small variant calls and describe how they were generated, in particular how we used WGS somatic calls to train a random forest classifier to detect variants in tumor-only RNA-seq. We also report all histopathological images used for medical diagnosis: hematoxylin and eosin–stained slides, brightfield images, and immunohistochemistry images of protein markers of clinical relevance. Conclusions This dataset will be critical to future studies relying on this PDTO biobank, such as drug screens for novel therapies and experiments investigating the mechanisms of carcinogenesis in these understudied diseases.

A signature event for organoids Human cancer genomes harbor cryptic mutational signatures that represent the cumulative effects of DNA damage and defects in DNA repair processes. Knowledge of how specific signatures originate could have a major impact on cancer diagnosis and prevention. One approach to address this question is to reproduce the signatures in experimental systems by genetic engineering and then match the signatures to those found in naturally occurring cancers. Drost et al. used CRISPR-Cas9 to delete certain DNA repair enzymes from human colon organoids. In a proof-of-concept study, they show that deficiency in base excision repair is responsible for a mutational signature previously identified in cancer genome sequencing projects. Science , this issue p. 234

Objectives Previous research established that emotional exhaustion - the often assumed core dimension of burnout - diminishes job-related functioning, but knowledge of its association with functioning and health care utilization is largely lacking. Moreover, as exhaustion frequently co-occurs with mood and anxiety disorders (i.e. common mental disorders (CMD)), the question should be addressed whether these associations hold after adjustment for CMD, and whether CMD intensifies the burden of exhaustion. Methods Cross-sectional data was used from 2902 workers included in the third wave of the Netherlands Mental Health Survey and Incidence Study-2, a nationally representative face-to-face survey. Exhaustion was assessed with the exhaustion scale of the Maslach Burnout Inventory; work loss (including presenteeism and absenteeism) with the WHO Disability Assessment Schedule; and general functioning with the 36-item Short Form. Health care use is defined as ≥1 general or mental health care contact for mental health problems. Confounders included sociodemographics, job characteristics, CMD, and physical health. The Composite International Diagnostic Interview assessed CMD. Results Mild and severe exhaustion occurred in 14.9% and 2.3% of the workers, respectively, and was significantly associated with work loss, impaired emotional, physical and social functioning, and health care use, even after adjustment for confounders. Co-occurrence of CMD strengthened the association between exhaustion and work loss as well as impaired emotional and social functioning. Conclusions Exhaustion is uniquely associated with work loss, impaired functioning and health care use. Moreover, co-occurring CMD intensified impairments in functioning. This stresses the need for clinical attention to the exhaustion dimension of burnout.

<p>PDF file - 674KB, Experimental design for the sorting of stem cells and TA cells from the duodenum of Lgr5-GFP-IRES-CreERT mice (Lgr5 Cre+ Catnb+/lox(ex3) Klf5flox/flox, Lgr5 Cre+ Catnb+/lox(ex3) Klf5+/+, and Lgr5 Cre+ Klf5flox/flox) for mRNA expression microarray analysis.</p>

Abstract BRCA1 germ-line mutations are a major cause of hereditary breast cancer and BRCA1-deficient breast cancer shares many characteristics as sporadic basal-like breast cancer (BLBC). Effective therapeutic targets for BRCA1-deficient BLBC remain lacking. By utilizing a BRCA1-deficient BLBC mouse model based on intraductal injection of Krt8-Cre adenovirus to inactivate Brca1 and Trp53 in luminal mammary epithelial cells, here we report that the Wnt receptor Frizzled 7 (FZD7) serves as a biomarker and therapeutic target in the resulting mammary tumor cells and is particularly enriched in cancer stem cells / tumor-initiating cells (CSCs/TICs). Inhibiting FZD7-mediated Wnt signaling using a nontoxic FZD-binding fragment of C. difficile toxin B (TcdBFBD) attenuates growth of BRCA1-deficient tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Finally, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both BLBC and luminal breast tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These findings demonstrate the therapeutic value for targeting FZD1/2/7 in treating breast cancers and establish TcdBFBD as a potential therapeutic agent targeting TICs and chemotherapy-resistant cancer cells.

Significance Influenza virus infection represents a major threat to public health worldwide. There is no biologically relevant, reproducible, and readily available in vitro model for predicting the infectivity of influenza viruses in humans. Based on the long-term expanding 3D human airway organoids, we developed proximal differentiation and further established a 2D monolayer culture of airway organoids. The resultant 3D and 2D proximal differentiated airway organoids can morphologically and functionally simulate human airway epithelium and as a proof of concept can discriminate human-infective influenza viruses from poorly human-infective viruses. Thus, the proximal differentiated airway organoids can be utilized to predict the infectivity of influenza viruses and, more broadly, provide a universal platform for studying the biology and pathology of the human airway.