Limitation and challenges in using pancreatic cancer-derived organoids as a preclinical tool.
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ABSTRACT:
SUBMITTER: Fraunhoffer NA
PROVIDER: S-EPMC9558692 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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Limitation and challenges in using pancreatic cancer-derived organoids as a preclinical tool.
Fraunhoffer Nicolas A NA Abuelafia Analía Meilerman AM Dusetti Nelson N Iovanna Juan J
Cancer communications (London, England) 20220718 10
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Project description:BackgroundOrganotypic 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.MethodsWe conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated in vivo. Patient-derived organoids were investigated as well.ResultsFirst, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array-based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small-scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. In vitro predictions were successfully validated in an in vivo xenograft trial. Translational proof-of-concept is exemplified in a patient with PDAC receiving palliative chemotherapy.ConclusionSmall-scale drug screening in organoids appears to be a feasible, robust and easy-to-handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting.
| S-EPMC7268941 | biostudies-literature
Project description:Background and purpose Pancreatic cancer (PC) is the fourth leading cause of cancer death in both men and women. The standard of care for patients with locally advanced PC of chemotherapy, stereotactic radiotherapy (RT), or chemo-radiation-therapy has shown highly variable and limited success rates. However, three-dimensional (3D) Pancreatic tumor organoids (PTOs) have shown promise to study tumor response to drugs, and emerging treatments under in vitro conditions. We investigated the potential for using 3D organoids to evaluate the precise radiation and drug dose responses of in vivo PC tumors. Methods PTOs were created from mouse pancreatic tumor tissues, and their microenvironment was compared to that of in vivo tumors using immunohistochemical and immunofluorescence staining. The organoids and in vivo PC tumors were treated with fractionated X-ray RT, 3-bromopyruvate (3BP) anti-tumor drug, and combination of 3BP + fractionated RT. Results Pancreatic tumor organoids (PTOs) exhibited a similar fibrotic microenvironment and molecular response (as seen by apoptosis biomarker expression) as in vivo tumors. Untreated tumor organoids and in vivo tumor both exhibited proliferative growth of 6 folds the original size after 10 days, whereas no growth was seen for organoids and in vivo tumors treated with 8 (Gray) Gy of fractionated RT. Tumor organoids showed reduced growth rates of 3.2x and 1.8x when treated with 4 and 6 Gy fractionated RT, respectively. Interestingly, combination of 100 µM of 3BP + 4 Gy of RT showed pronounced growth inhibition as compared to 3-BP alone or 4 Gy of radiation alone. Further, positive identification of SOX2, SOX10 and TGFβ indicated presence of cancer stem cells in tumor organoids which might have some role in resistance to therapies in pancreatic cancer. Conclusions PTOs produced a similar microenvironment and exhibited similar growth characteristics as in vivo tumors following treatment, indicating their potential for predicting in vivo tumor sensitivity and response to RT and combined chemo-RT treatments.
| S-EPMC9879007 | biostudies-literature
Project description:Lumens are crucial features of the tissue architecture in both the healthy exocrine pancreas, where ducts shuttle enzymes from the acini to the intestine, and in the precancerous lesions of the highly lethal pancreatic ductal adenocarcinoma (PDAC), similarly displaying lumens that can further develop into cyst-like structures. Branched pancreatic-cancer derived organoids capture key architectural features of both the healthy and diseased pancreas, including lumens. However, their transition from a solid mass of cells to a hollow tissue remains insufficiently explored. Here, we show that organoids display two orthogonal but complementary lumen formation mechanisms: one relying on fluid intake for multiple microlumen nucleation, swelling and fusion, and the other involving the death of a central cell population, thereby hollowing out cavities. These results shed further light on the processes of luminogenesis, deepening our understanding of the early formation of PDAC precancerous lesions, including cystic neoplasia.
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Project description:ObjectiveAdvanced cervical cancer is still difficult to treat and in the case of recurrent cancer, it is desirable to utilize personalized treatment rather than uniform treatment because the type of recurrence is different for each individual. Therefore, this study aimed to establish a patient-derived organoid (PDO) platform to determine the effects of chemotherapy, radiation therapy, and targeted therapy in cervical cancer.MethodsWe established organoids from 4 patients with various types of cervical cancer. The histopathological and gene profiles of these organoid models were compared to determine their characteristics and the maintenance of the patient phenotype. Each type of organoid was also subjected to anticancer drug screening and radiation therapy to evaluate its sensitivity.ResultsWe established PDOs to recapitulate the main elements of the original patient tumors, including the DNA copy number and mutational profile. We selected 7 drugs that showed growth inhibition in cervical cancer organoids out of 171 using an Food and Drug Administration -approved drug library. Moreover, adenocarcinoma and large-cell neuroendocrine carcinoma showed resistance to radiation therapy. whereas squamous cell carcinoma and villoglandular carcinoma showed a significant response to radiotherapy.ConclusionOur results showed that patient-derived cervical cancer organoids can be used as a platform for drug and radiation sensitivity testing. These findings suggest that patient-derived cervical cancer organoids could be used as a personalized medicine platform and may provide the best treatment options for patients with various subtypes of cervical cancer.
| S-EPMC10157333 | biostudies-literature
Project description:Pancreatic cancer is a devastating disease and is highly resistant to anticancer drugs because of its complex microenvironment. Cancer-associated fibroblasts (CAFs) are an important source of extracellular matrix (ECM) components, which alter the physical and chemical properties of pancreatic tissue, thus impairing effective intratumoral drug delivery and resulting in resistance to conventional chemotherapy. The objective of this study was to develop a new cancer organoid model, including a fibrous tumor microenvironment (TME) using CAFs. The CAF-integrated pancreatic cancer organoid (CIPCO) model developed in this study histologically mimicked human pancreatic cancer and included ECM production by CAFs. The cancer cell-CAF interaction in the CIPCO promoted epithelial-mesenchymal transition of cancer cells, which was reversed by CAF inhibition using all-trans retinoic acid. Deposition of newly synthesized collagen I in the CIPCO disturbed the delivery of gemcitabine to cancer cells, and treatment with collagenase increased the cytotoxic effect of gemcitabine. This model may lead to the development of next-generation cancer organoid models recapitulating the fibrous TME.
| S-EPMC9103557 | biostudies-literature
Project description:Epithelial ovarian cancer (EOC) remains the most lethal gynecological cancer in developed countries, indicating the need for further research. Although current cancer models prove useful, they have major limitations. Organoids, a novel in vitro 3D cell culture technique, derived from stem cells, could provide a bridge between the current preclinical platforms. However, this technique is still in its early stages. After conducting a systematic literature search, only sixteen manuscripts concerning ovarian related organoids could be retrieved.In this review, we discuss current tumor models, including organoids and provide a comprehensive review about organoids of ovarian tissue. Potential future applications are addressed, proving organoids to be an interesting platform for modeling tumorigenesis, drug testing and screening and other applications. Recent advancements could usher in a new era of highly personalized medicine in EOC.
| S-EPMC6839218 | biostudies-literature
Project description:ObjectiveTo evaluate if patient-derived organoids (PDOs) may predict response to neoadjuvant (NAT) chemotherapy in patients with pancreatic adenocarcinoma.BackgroundPDOs have been explored as a biomarker of therapy response and for personalized therapeutics in patients with pancreatic cancer.MethodsDuring 2017-2021, patients were enrolled into an IRB-approved protocol and PDO cultures were established. PDOs of interest were analyzed through a translational pipeline incorporating molecular profiling and drug sensitivity testing.ResultsOne hundred thirty-six samples, including both surgical resections and fine needle aspiration/biopsy from 117 patients with pancreatic cancer were collected. This biobank included diversity in stage, sex, age, and race, with minority populations representing 1/3 of collected cases (16% Black, 9% Asian, 7% Hispanic/Latino). Among surgical specimens, PDO generation was successful in 71% (15 of 21) of patients who had received NAT prior to sample collection and in 76% (39 of 51) of patients who were untreated with chemotherapy or radiation at the time of collection. Pathological response to NAT correlated with PDO chemotherapy response, particularly oxaliplatin. We demonstrated the feasibility of a rapid PDO drug screen and generated data within 7 days of tissue resection.ConclusionHerein we report a large single-institution organoid biobank, including ethnic minority samples. The ability to establish PDOs from chemotherapy-naive and post-NAT tissue enables longitudinal PDO generation to assess dynamic chemotherapy sensitivity profiling. PDOs can be rapidly screened and further development of rapid screening may aid in the initial stratification of patients to the most active NAT regimen.
| S-EPMC10202108 | biostudies-literature
Project description:BackgroundThe effectiveness of radiotherapy for pancreatic cancer is debated. Patient-derived organoids (PDOs) already mimicked clinical radiation response in other cancer types, which could be valuable in pancreatic cancer as well. This study aimed to investigate whether PDOs can be used to model RT response in pancreatic cancer and to explore the presence of a dose-response correlation.MethodsPDOs derived from two pancreatic cancer patients (HUB-08-B2-022A and HUB-08-B2-026B) were irradiated with doses ranging from 0 to 40 Gray. Viability assessments were conducted after seven and 10 days by measuring ATP-levels. Results were normalized, defining the viability at 0 Gray as 100 % and an absolute viability of 0 as 0 %. The relative area under the curve (rAUC) was calculated (0 = total sensitivity, 1 = total resistance).ResultsWith a readout time of seven days, both HUB-08-B2-022A and HUB-08-B2-026B exhibited viability above 50 % at the highest dose of 12 Gy (rAUC of 0.79 and 0.69, respectively). With a readout time of 10 days, both PDOs showed a dose-response relation although HUB-08-B2-022A was more sensitive than HUB-08-B2-026B (rAUC of 0.37 and 0.51, respectively). Increasing the radiation dose to 40 Gy did not further affect viability, but the dose-response relation remained present (rAUC of 0.13 and 0.26, respectively). In the final experiment with a readout time of 10 days and a maximum dose of 14 Gy, the dose-response correlation was paramount in both PDOs (rAUC 0.28 and 0.45, respectively), with HUB-08-B2-022A being most sensitive.ConclusionsIn this setup, both pancreatic cancer PDOs showed an irradiation dose-response correlation. These preliminary findings suggest that pancreatic cancer PDOs are suitable for assessing radiation response in vitro. Further experiments are needed to eventually simulate treatment responses to personalized treatment strategies.
| S-EPMC11347840 | biostudies-literature
Project description:Patient-derived organoids are being considered as models that can help guide personalized therapy through in vitro anticancer drug response evaluation. However, attempts to quantify in vitro drug responses in organoids and compare them with responses in matched patients remain inadequate. In this study, we investigated whether drug responses of organoids correlate with clinical responses of matched patients and disease progression of patients. Organoids were established from 54 patients with colorectal cancer who (except for one patient) did not receive any form of therapy before, and tumor organoids were assessed through whole-exome sequencing. For comparisons of in vitro drug responses in matched patients, we developed an 'organoid score' based on the variable anticancer treatment responses observed in organoids. Very interestingly, a higher organoid score was significantly correlated with a lower tumor regression rate after the standard-of-care treatment in matched patients. Additionally, we confirmed that patients with a higher organoid score (≥ 2.5) had poorer progression-free survival compared with those with a lower organoid score (< 2.5). Furthermore, to assess potential drug repurposing using an FDA-approved drug library, ten tumor organoids derived from patients with disease progression were applied to a simulation platform. Taken together, organoids and organoid scores can facilitate the prediction of anticancer therapy efficacy, and they can be used as a simulation model to determine the next therapeutic options through drug screening. Organoids will be an attractive platform to enable the implementation of personalized therapy for colorectal cancer patients.
| S-EPMC9208081 | biostudies-literature
Project description:Pancreatic cancer (PC) is a fatal malignancy in the human abdominal cavity that
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