Abstract:There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In … Show more
“…Among the CISS images that contained attachment with the dura mater, the maximum area and perimeter at the same slice were measured. FF was calculated as (4π × area)/perimeter 2 , where FF = 1 indicates a perfect circle and FF = 0 indicates a straight line (28).…”
“…Among the CISS images that contained attachment with the dura mater, the maximum area and perimeter at the same slice were measured. FF was calculated as (4π × area)/perimeter 2 , where FF = 1 indicates a perfect circle and FF = 0 indicates a straight line (28).…”
“…However, testing of these findings in novel human cancer models reflecting the whole heterogeneity spectrum of the disease is necessary. Here, the recent development of human organoid PDAC models (82,83) will provide an appropriate platform to further develop MYC inhibitors and MYC-based therapeutic concepts in human disease models.…”
Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC.
“…In an attempt to address some of these fundamental flaws, new methods using stem-cell based organoid models, tissue engineering or sophisticated 3D cell culture models have been established 30,31 . However, these methods are also quite complex and expensive and cannot replace systemic toxicity tests in living organisms.…”
The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressingFirefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations.With less than 7% of patients alive five years after diagnosis, pancreatic ductal adenocarcinoma (PDAC) exhibits one of the poorest prognoses of all solid tumors. Despite extensive clinical efforts, the outcome of this malignancy has not improved in the last decade, and PDAC is expected to become the second deadliest cancer, after lung cancer, by 2030 1,2 .Gaining more insight into the mechanisms that delineate tumor progression in PDAC could ultimately provide more successful therapeutic approaches. To this end, genetically engineered mouse models (GEMMs) have provided a powerful tool, developing tumors that recapitulate both the underlying biology and the dense desmoplastic reaction of PDACs. This stromal reaction has been considered for years as one of the mediators of resistance to chemotherapy 3 . However, experimental and clinical evidence demonstrated that anti-stromal approaches may favour PDAC aggressiveness, reinforcing the need to critically revisit the complexity of cancer-stroma interactions for translational and pharmacological implications 4 . Recent studies suggested that early passages of primary PDAC cells and "avatar" mice can mimic the genetic diversity that characterizes the human disease and might be better predictors of drug activity, including the standard treatment with gemcitabine 5,6 .Despite several studies used such in vivo models in order to promote drug development and selection, their costs and complexity impaired the translation of these results in the clinical setting. Novel, cost-effective models that similarly mimic tumor biology and provide faster information on the activ...
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