Comparative analysis of patient-derived organoids and patient-derived xenografts as avatar models for predicting response to anti-cancer therapy.

Patient-derived xenografts (PDX) and organoids (PDO) are widely used to model cancer and predict treatment response in matched patients. However, their predictive accuracy has not been systematically studied nor compared. We conducted a systematic review and meta-analysis of studies using PDX or PDO from solid tumors treated with identical anti-cancer agents as the matched patient, identifying 411 patient-model pairs (267 PDX, 144 PDO).

Homologous Repair-Deficient Pancreatic Cancer: Refined Targeting of DNA Damage Response is an Effective Therapeutic Strategy.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a high mortality rate. While up to 20% of PDAC patients harbor mutations in genes involved in homologous recombination (HR) repair, only 5% of germline BRCA1/2 mutation carriers have an approved treatment option with the PARP inhibitor (PARPi) olaparib. Characterizing HR-deficient (HRD) genotypes beyond gBRCA1/2 that are susceptible to PARPi has potential to substantially broaden the eligible patient population, and defining the optimal inhibitor may further optimize treatment strategies to advance personalized medicine in PDAC.

Pancreatic organoids as cancer avatars for true personalized medicine.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal solid malignancy, rapidly progressing and highly therapeutic resistant, as reflected by its very low five-year overall survival. Despite significant advancements in our understanding of its pathobiology and the molecular mechanisms driving its tumorigenesis, therapeutic options remain limited and yield only modest clinical responses. PDAC is characterized by a high genetic inter and intratumoral heterogeneity that shapes its mutational landscape and affects its response to therapies.

Organoid-based precision medicine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) ranks among the leading causes of cancer-related deaths worldwide. Despite advances in precision oncology in other malignancies, treatment of PDAC still largely relies on conventional chemotherapy. Given the dismal prognosis and heterogeneity in PDAC, there is an urgent need for personalized therapeutic strategies to improve treatment response.

RBPJ Deficiency Sensitizes Pancreatic Acinar Cells to KRAS-Mediated Pancreatic Intraepithelial Neoplasia Initiation.

Background And Aims: Development of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary.

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.

A Methodological Workflow to Analyze Synthetic Lethality and Drug Synergism in Cancer Cells.

Current concepts in treating cancer usually neglect individual tumor characteristics such as a given mutational make up. Consequently, a "one-size-fits-all" therapeutic concept may commonly fail in terms of efficacy, evolving drug resistance, and side effects. In times of omics, novel elaborated and personalized approaches emerge for efficiently eradicate cancer cells, while sparing healthy cells.

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.

Targeting DNA Damage Repair Mechanisms in Pancreas Cancer.

Impaired DNA damage repair (DDR) is increasingly recognised as a hallmark in pancreatic ductal adenocarcinoma (PDAC). It is estimated that around 14% of human PDACs harbour mutations in genes involved in DDR, including, amongst others, , , , , and . Recently, DDR intervention by PARP inhibitor therapy has demonstrated effectiveness in germline -mutated PDAC.

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids.

A Prospective Feasibility Trial to Challenge Patient-Derived Pancreatic Cancer Organoids in Predicting Treatment Response.

Real-time isolation, propagation, and pharmacotyping of patient-derived pancreatic cancer organoids (PDOs) may enable treatment response prediction and personalization of pancreatic cancer (PC) therapy. In our methodology, PDOs are isolated from 54 patients with suspected or confirmed PC in the framework of a prospective feasibility trial. The drug response of single agents is determined by a viability assay.

RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC.

Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy.

Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline -mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear.

Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer.

Objective: (ATM) is the most frequently mutated DNA damage response gene, involved in homologous recombination (HR), in pancreatic ductal adenocarcinoma (PDAC).

Design: Combinational synergy screening was performed to endeavour a genotype-tailored targeted therapy.

Results: Synergy was found on inhibition of PARP, ATR and DNA-PKcs (PAD) leading to synthetic lethality in ATM-deficient murine and human PDAC.

IFN-γ treatment protocol for MHC-I/PD-L1 pancreatic tumor cells selectively restores their TAP-mediated presentation competence and CD8 T-cell priming potential.

Background: Many cancer cells express a major histocompatibility complex class I low/ programmed cell death 1 ligand 1 positive (MHC-I/PD-L1) cell surface profile. For immunotherapy, there is, thus, an urgent need to restore presentation competence of cancer cells with defects in MHC-I processing/presentation combined with immune interventions that tackle the tumor-initiated PD-L1/PD-1 signaling axis. Using pancreatic ductal adenocarcinoma cells (PDACCs) as a model, we here explored if (and how) expression/processing of tumor antigens via transporters associated with antigen processing (TAP) affects priming of CD8 T cells in PD-1/PD-L1-competent/-deficient mice.

DNA damage repair as a target in pancreatic cancer: state-of-the-art and future perspectives.

Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR).

Pancreatic cancer-derived organoids - a disease modeling tool to predict drug response.

Background: Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date.

Methods: We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization.

MEK Inhibition Targets Cancer Stem Cells and Impedes Migration of Pancreatic Cancer Cells and .

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a very poor prognosis. At the same time, its incidence is on the rise, and PDAC is expected to become the second leading cause of cancer-related death by 2030. Despite extensive work on new therapeutic approaches, the median overall survival is only 6-12 months after diagnosis and the 5-year survival is less than 7%.

Pancreatic Ductal Organoids React Kras Dependent to the Removal of Tumor Suppressive Roadblocks.

Pancreatic ductal adenocarcinoma (PDAC) is still the Achilles heel in modern oncology, with an increasing incidence accompanied by a persisting high mortality. The developmental process of PDAC is thought to be stepwise via precursor lesions and sequential accumulation of mutations. Thereby, current sequencing studies recapitulate this genetic heterogeneity in PDAC and show besides a handful of driver mutations (KRAS, TP53) a plethora of passenger mutations that allow to define subtypes.

Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS-driven Pancreatic Tumorigenesis.

Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive.

Lysyl oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution.

Solid tumors often display chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of resistant tumors as current chemotherapies are inefficient. The tumor stroma and extracellular matrix (ECM) are key contributors to PDAC aggressiveness and to limiting the efficacy of chemotherapy.

TIF1γ Suppresses Tumor Progression by Regulating Mitotic Checkpoints and Chromosomal Stability.

The transcription accessory factor TIF1γ/TRIM33/RFG7/PTC7/Ectodermin functions as a tumor suppressor that promotes development and cellular differentiation. However, its precise function in cancer has been elusive. In the present study, we report that TIF1γ inactivation causes cells to accumulate chromosomal defects, a hallmark of cancer, due to attenuations in the spindle assembly checkpoint and the post-mitotic checkpoint.

Isolation and culture of mouse primary pancreatic acinar cells.

This protocol permits rapid isolation (in less than 1 hr) of murine pancreatic acini, making it possible to maintain them in culture for more than one week. More than 20 x 10(6) acinar cells can be obtained from a single murine pancreas. This protocol offers the possibility to independently process as many as 10 pancreases in parallel.