Prospective pharmacotyping of urothelial carcinoma organoids for drug sensitivity prediction - feasibility and real world experience.

Urothelial carcinoma (UC) of the urinary bladder has significant challenges in treatment due to its diverse genetic landscape and variable response to systemic therapy. In recent years, patient-derived organoids (PDOs) emerged as a novel tool to model primary tumors with higher resemblance than conventional 2D cell culture approaches. However, the potential of organoids to predict therapy response in a clinical setting remains to be evaluated.

Pancreatic acinar heterogeneity hijacks carcinogenesis and homeostasis.

In this issue, Jiang and colleagues employ multiple lineage-tracing approaches to elaborate on the role of Tff2+ transit-amplifying progenitor cells in the pancreatic acinar compartment of mice. This work provides insights into the steady-state homeostasis and tumor-suppressive features of certain progenitor cells and presents findings on acinar cell heterogeneity.

Single-cell profiling of GP2-enriched pancreatic progenitors to simultaneously create acinar, ductal, and endocrine organoids.

Pancreatic lineage specification follows the formation of tripotent pancreatic progenitors (PPs). Current protocols rebuilding PPs have an endocrine lineage bias and are mostly based on PDX1/NKX6-1 coexpression neglecting other markers decisive for PP heterogeneity and lineage potential. However, true tripotent PPs are of utmost interest to study also exocrine disorders such as pancreatic cancer and to simultaneously generate all three pancreatic lineages from the same ancestor.

The application of pancreatic cancer organoids for novel drug discovery.

Introduction: Pancreatic ductal adenocarcinoma presents with a dismal prognosis. Personalized therapy is urgently warranted to overcome the treatment limitations of the 'one-size-fits-all' scheme. Organoids have emerged as fundamental novel tools to study tumor biology and heterogeneity, hence overcoming limitations of other model systems by better-reflecting tissue heterogeneity and recapitulating in-vivo processes.

TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration.

Background: The reactivation of genetic programs from early development is a common mechanism for injury-induced organ regeneration. T-box 3 (TBX3) is a member of the T-box family of transcription factors previously shown to regulate pluripotency and subsequent lineage commitment in a number of tissues, including limb and lung. TBX3 is also involved in lung and heart organogenesis.

Protocol to use de-epithelialized porcine urinary bladder as a tissue scaffold for propagation of pancreatic cells.

Ex vivo organ culture can be a useful alternative to in vivo models, which can be time-, labor-, and cost-intensive. Here we describe a step-by-step protocol to use de-epithelialized porcine urinary bladders as scaffolds in air-liquid interface in vitro culture systems for a variety of pluripotent stem-cell-derived and patient-derived pancreatic cells and organoids. The scaffold can trigger cell maturation and enable cell-cell interaction and invasion capacity studies.

[Organoids as a milestone on the way to personalized treatment of urothelial carcinoma: a systematic review].

Background: The treatment options for locally advanced and metastatic urothelial carcinoma (UC) are currently limited to established chemotherapy and immunotherapy protocols. Targeted treatment is so far restricted to a small subgroup of patients. Urothelial organoid systems could make a decisive contribution in establishing effective personalized treatment options by enabling drug response prediction through testing the sensitivity of individual patients.

State-matched organoid models to fight pancreatic cancer.

As one of the deadliest cancers, pancreatic ductal adenocarcinoma (PDAC) requires sophisticated model systems to dissect disease onset, progression, and therapy resistance, as well as to personalize therapy. In recent years, patient- and pluripotent stem cell-derived organoids have become state-of-the-art systems to refine existing therapeutic strategies and deepen our knowledge of disease pathophysiology.

Organoids at the PUB: The Porcine Urinary Bladder Serves as a Pancreatic Niche for Advanced Cancer Modeling.

Despite intensive research and progress in personalized medicine, pancreatic ductal adenocarcinoma remains one of the deadliest cancer entities. Pancreatic duct-like organoids (PDLOs) derived from human pluripotent stem cells (PSCs) or pancreatic cancer patient-derived organoids (PDOs) provide unique tools to study early and late stage dysplasia and to foster personalized medicine. However, such advanced systems are neither rapidly nor easily accessible and require an in vivo niche to study tumor formation and interaction with the stroma.

Differentiation of human pluripotent stem cells into pancreatic duct-like organoids.

The recapitulation of human developmental processes and pathological manifestations requires access to specific cell types and precursor stages during embryogenesis and disease. Here, we describe a scalable differentiation protocol to guide human pluripotent stem cells stepwise into pancreatic duct-like organoids. The protocol mimics pancreatic duct development and was successfully used to model the onset and progression of pancreatic ductal adenocarcinoma; the approach is suitable for multiple downstream applications.

Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants.

Diabetes, as one of the major diseases in industrial countries, affects over 350 million people worldwide. Type 1 (T1D) and type 2 diabetes (T2D) are the most common forms with both types having invariable genetic influence. It is accepted that a subset of all diabetes patients, generally estimated to account for 1-2% of all diabetic cases, is attributed to mutations in single genes.

An Immunological Glance on Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has still a dismal prognosis. Different factors such as mutational landscape, intra- and intertumoral heterogeneity, stroma, and immune cells impact carcinogenesis of PDAC associated with an immunosuppressive microenvironment. Different cell types with partly opposing roles contribute to this milieu.

Enhanced Safety and Efficacy of Oncolytic VSV Therapy by Combination with T Cell Receptor Transgenic T Cells as Carriers.

Vesicular stomatitis virus (VSV) represents an attractive oncolytic virotherapy platform because of its potent tumor cell-killing and immune-stimulating properties; yet the clinical translation of VSV faces numerous challenges, such as inefficient systemic delivery and severe side effects such as neurotoxicity. We hypothesized that we could overcome these limitations and simultaneously enhance the therapy, by combining VSV with adoptively transferred T cell receptor (TCR) transgenic T cells as carrier cells. We show that CD8 T central memory cells (CD8 T cm) can be efficiently loaded with VSV, they support intracellular virus production, and they can efficiently transfer VSV to tumor cells without compromising their own viability or antitumor reactivity.

Oncolytic Vesicular Stomatitis Virus as a Viro-Immunotherapy: Defeating Cancer with a "Hammer" and "Anvil".

Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV), a negative-strand RNA virus, is under intense development as an oncolytic virus due to a variety of favorable properties, including its rapid replication kinetics, inherent tumor specificity, and its potential to elicit a broad range of immunomodulatory responses to break immune tolerance in the tumor microenvironment. Based on this powerful platform, a multitude of strategies have been applied to further improve the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect.