Publications

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During germinal center (GC) reactions, activated B cells undergo clonal expansion and functional maturation to produce high-affinity antibodies and differentiate into plasma and memory cells, accompanied with class-switching recombination (CSR) and somatic hypermutation (SHM). Activation-induced cytidine deaminase (AID) is responsible for both CSR and SHM in GC B cells. Transcriptional mechanisms underlying AID regulation and GC B cell reactions are still not well understood. Here, we show that expression of Ascl2 transcription factor is upregulated in GC B cells. Ectopic expression of Ascl2 promotes GC B cell development and enhances antibody production and affinity maturation. Conversely, deletion of Ascl2 in B cells impairs the GC response. Genome-wide analysis reveals that Ascl2 directly regulates GC B cell-related genes, including AID; ectopic expression of AID in Ascl2-deficient B cells rescues their antibody defects. Thus, Ascl2 regulates AID transcription and promotes GC B cell responses.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.

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No abstract is provided for this article.

<p>Figure S6. IHC for b-catenin, Myc, gastrin and Muc5a in Apc.Fzd7.TffCre adenoma tissue.</p>

Facial shaping results from oriented divisions and crowd movements of ectomesenchymal cells during morphogenetic events.

<div>Abstract<p>Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient–derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.</p><p><b>Significance:</b> New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. <i>Cancer Discov; 8(9); 1112–29. ©2018 AACR.</i></p><p><i>See related commentary by Collisson, p. 1062</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1047</i></p></div>

<p>Cell-cell interaction output T/NK vs. myeloid cells</p>

Significance Multiple myeloma (MM) cells are highly dependent on signals provided by the bone marrow (BM) niche for growth and survival. Most MMs display hallmarks of active Wnt signaling, but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the BM niche. In this study we uncover a pivotal role for the leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4)/R-spondin axis in facilitating activation of Wnt signaling in MM. LGR4 is expressed by most MMs, but not by healthy plasma cells, and is regulated by STAT3 signaling. LGR4 expression allows MMs to respond to (pre)osteoblast–derived R-spondins, resulting in stabilization of Wnt receptors and greatly enhanced sensitivity to auto- and paracrine Wnt ligands. These results advocate targeting of proximal Wnt signaling in MM.

Abstract Background Pediatric Inflammatory Bowel Disease (IBD) is a chronic condition characterized by persistent intestinal inflammation in children. It often presents with distinct clinical phenotypes and is more frequently linked to rare monogenic variants affecting epithelial barrier function or mucosal immunity. Although over 100 genes are associated with monogenic IBD, their roles in the intestinal epithelium remain poorly defined. This study aimed to improve our understanding of epithelial dysfunction in early-onset IBD through molecular and cellular analyses to uncover patient-specific phenotypes and potential therapeutic targets. Methods We generated intestinal epithelial organoids (IEOs) from 94 pediatric IBD patients, including those with monogenic variants (BTK, TTC7A, IL10RA, LRBA, STXBP2, TRNT1, SKIV2L), along with 46 non-IBD controls. RNA sequencing was performed on 38 patient and 20 control lines, under both baseline conditions and after immunological stimulation, yielding a valuable dataset for studying epithelial responses in IBD. Results IEOs effectively initiated inflammation upon bacterial lysate stimulation, regardless of disease status, origin, or genotype. Inflammatory stimulation triggered upregulation of IBD-linked genes SERPINA1 and LIFR in IBD organoids, suggesting their role in epithelial innate immunity. However, network analysis showed no consistent transcriptional signatures across all IBD cases. Instead, specific genotypes (TTC7A, STXBP2, LRBA) revealed responses, with STXBP2 and LRBA showing shared upregulation of IL-1 and SLC30-mediated zinc trafficking pathways. Conclusions These findings underscore the potential of IEOs as a valuable model for studying IBD and offer key insights that could guide the development of targeted therapies for both monogenic and non-monogenic forms of IBD.