Nowadays, the diagnosis and treatment system of malignant tumors has increasingly tended to be more precise and personalized while the existing tumor models are still unable to fully meet the needs of clinical practice. Notably, the emerging organoid platform has been proven to have huge potential in the field of basic-translational medicine, which is expected to promote a paradigm shift in personalized medicine. Here, given the unique advantages of organoid platform, we mainly explore the prominent role of organoid models in basic research and clinical practice from perspectives of tumor biology, tumorigenic microbes-host interaction, clinical decision-making, and regenerative strategy. In addition, we also put forward some practical suggestions on how to construct a new generation of organoid platform, which is destined to vigorously promote the reform of basic-translational medicine. 

Organoid: Bridging the gap between basic research and clinical practice.


 Introduction: Pancreatic adenocarcinoma (PDAC) has a 5-year survival rate of ~10%. Only 20% of patients are eligible for surgical resection, while the remaining patients treated with chemotherapy who show poor response. It is critical to define mechanisms that accurately predict patient responses to established or novel therapies. We are developing living biobanks of patient-derived organoids (PDOs) and Cancer-Associated Fibroblast (CAFs) from endoscopic ultrasound (EUS) and focusing on epigenetic regulators which may account for resistance. Recent studies implicate both CAFs and epigenetic regulators in resistance to chemotherapy and highlight the importance of epigenetic regulation independent of gene mutations. We hypothesize that PDOs can be used to define molecular events that will determine patient-specific sensitivities to therapy. Our goals are to (1) establish parameters within PDOs that predict patient response and (2) target epigenetic processes that may uncover sensitivities to therapy. Methods: To develop a living biobank, patients were consented into the DERIVE (Determination of Response to Therapy in Individual Patients) program (REB#113362). Needle biopsies were obtained during EUS resection. CAFs and tumor cells were isolated and grown in 2- or 3-D cultures respectively. We performed histological analysis and isolated DNA for ONCOMINE sequencing to analyze somatic mutations of each PDOs. To determine the relative sensitivity, PDOs were treated with gemcitabine and IC50 values determined using Alamar blue. PDO attributes were then compared to the DERIVE database. We determined CAFs subpopulation by immunofluorescence and flow cytometry. Results: ONCOMINE sequencing showed PDOs genetic mutations were conserved according to patient tumor analysis. PDOs showed different morphological characteristics and we identified groups of gemcitabine-sensitive and resistant PDOs which is not reflected by genetic mutations. Treated and non-treated PDOs are currently being assessed for global DNA-methylation patterns and ATAC-seq to identify changes in chromatin remodeling. In addition, two major subpopulations of CAFs were identified: myCAFs and iCAFs. These subpopulations will be co-cultured with PDOs and treated to chemotherapies to determine the impact of each subpopulation on chemoresistance and analyze by ATAC-Seq to determine the epigenetic regulator that is involved in chemoresistance mechanism. Conclusions and Future Directions: By aligning our findings in PDOs to the DERIVE database, we defined parameters that predict disease progression and the patients’ response to chemotherapy. To identify epigenetic modifications, we examined global genetic and epigenomic patterns in PDOs before and after treatment with chemotherapeutic agents as well as in co-cultured with different CAFs subpopulation. This work will determine if epigenetic mechanisms can be targeted as a new approach to therapy. This work highlights the importance of PDOs as a valuable model in identifying the best choices for treatment in PDAC cancer.
 Citation Format: Emilie Jaune-Pons, Rachel Lu, Xiao Yang Wang, Nadeem Hussain, Michael Sey, Ken Leslie, Ephraim Tang, Anton Skaro, Crystal Engelage, Danielle Porplycia, Stephen Welch, Brian Yan, Christopher Pin. Epigenetic characterization of patient-derived organoids and cancer-associated fibroblasts from endoscopic ultrasound of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B029.

Abstract B029: Epigenetic characterization of patient-derived organoids and cancer-associated fibroblasts from endoscopic ultrasound of pancreatic cancer

Assessment of skeletal maturity is paramount for orthodontists since optimal use and effectiveness of orthodontic and orthopedic appliances depends on it. Objective: To compare the cervical vertebral maturation (CVM) with Fishman’s hand wrist radiograph (HWR) method in assessment of growth status. Methods: This comparative cross sectional study was conducted at the Orthodontics department at the Khyber College of dentistry, Peshawar on 100 participants. The patients with 9 to 15 years of age, relatively well aligned arches, both genders, mild to moderate skeletal discrepancy, minimal dental compensations, vertical normal angle, and without temporomandibular joint disorders were included. Along with age and gender, stages of HWR and CVM were recorded.  HWRs were acquired by standardized method and lateral cephalograms were taken in natural head position.  The staging of HWR was done by using Fishman method while CVM staging. Comparison of CVM stages and Fishmann’s HWR stages were done using chi-square test. Results: The mean age was 11.79 ± 1.62 years.   The females were 53(53%) and males were 47(47%). Most common stage of CVM was III (n=33, 33%) followed by IV (n=27, 27%). Similarly, common stage of hand wrist radiograph was III (n=32, 32%) followed by IV (n=28, 28%).There was no statistically significant different between two methods for assessing skeletal growth status (p=0.697). Conclusions: Cervical vertebral maturation can have used as an alternative to hand wrist radiograph for growth assessment without an extra radiation

Comparison of Cervical Vertebral Maturation with Fishman’s Skeletal Maturity Index Method in Assessment of Growth Status


 Background and study aims  The aim of this study was to investigate the impact of delayed endoscopic mucosal resection (EMR) of colorectal polyps on health outcomes. Patients and methods  A bidirectional cohort study was completed. A baseline group consisting of all EMRs performed within a 15-month period before a province-wide, government-mandated cessation of EMR procedures due to the global pandemic was compared to EMRs impacted by the shutdown, defined as the COVID-19-delayed group. The primary outcome was the incidence of malignant polyps. Secondary outcomes included technical success, polyp recurrence at follow-up colonoscopy, advanced polyp histology, probability of meeting endoscopic criteria for adequate resection for malignant polyps, metastatic colorectal cancer, and complications. Results  A total of 268 EMR procedures were included in the study cohort, of which 208 formed the baseline group and 60 were in the COVID-19-delayed group. The median (IQR) patient age was 72 (13.0) and 113 (41.2 %) were females. The median (IQR) wait time was 92 days (87.8) in the baseline group and 191 days (127.8) in the COVID-19-delayed group ( P  < 0.001). Overall, there were no significant differences in the incidence of malignant polyps, technical success, polyp recurrence on follow-up colonoscopy, advanced polyp histology, adequate endoscopic resection for malignant polyps, metastatic colorectal cancer, or complications between the two groups ( P  > 0.05 for all outcomes). Conclusions  A longer wait time for EMR of colorectal polyps, increasing from a median of 92 to 191 days, was not associated with worse outcomes.


/pdf/extended-delay-in-endoscopic-mucosal-resection-is-not-2gc5ps6x.pdf

Extended delay in endoscopic mucosal resection is not associated with adverse outcomes: Findings from the COVID-19 pandemic


 Pancreatic adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in Canada with a 5-year survival rate ~10%. Unfortunately, only 20% of patients are eligible for surgical resection while the other 80% of patients are treated with chemotherapy (i.e. nab-paclitaxel, Gemcitabine, or FOLFIRINOX) that shows limited efficiency. Also, the tumor microenvironment (TME), and specifically cancer-associated fibroblasts (CAFs), contribute to PDAC chemoresistance. Recent studies suggest heterogeneity of CAF subtypes in patients, including myofibroblast (my), inflammatory (i), and antigen-presenting (ap) CAFs, is linked to more aggressive PDAC. While there is clear evidence CAFs effect tumor growth, chemoresistance and metastasis, the mechanisms underlying these effects are unknown. Given the involvement of environmental cues from the TME and the recent literature involving HDACs and epigenetic regulators in chemoresistance, we propose epigenetic reprogramming occurs in pancreatic cancer cells in response to CAFs, thereby affecting their response to chemotherapy. Using patient-derived tumor cells we examine the cross talk that occurs between cancer cells and CAFs in a patient-specific manner. We hypothesized that patient-specific CAF populations alter cancer cell phenotypes and chemosensitivity through epigenetic reprograming. Supported by the Baker Centre for Pancreatic Cancer, we established a living biobank of patient-derived organoids (PDO) grown in 3D cultures and CAFs grown in 2D cultures. These samples are linked to DERIVE (Determination of Response to Therapy in Individual Patients), a clinical database that includes patient response to therapy. Characterization of low passage, patient CAFs by flow cytometry shows significant heterogeneity between samples based on the proportions of myCAFs, iCAFs and apCAFs, and also identified CAFs that do not belong to any of these subtypes. Incubation of PDOs with CAF-conditioned media showed an increase in growth regardless of the CAF samples but, interestingly, myCAF-high (myCAFHI) conditioned media promoted a cystic-like phenotype in PDOs while iCAF-high conditioned media promoted a more complex PDO phenotype. myCAFHI-conditioned media also sensitized resistant PDOs to gemcitabine. Characterization of epigenetic mediators showed variable expression of histone deacetylases (HDACs), and combinatorial treatment with gemcitabine and the HDAC5 inhibitor, LMK-235 sensitized resistant PDOs to gemcitabine. We are currently performing single-cell RNA-seq, ATAC-seq and DNA methylation profiling on PDOs before and after treatment with CAF-conditioned media to identify unique CAF populations and examine the epigenetic targets underlying these outcomes. This study (1) shows CAFs present with significant heterogeneity between patients and secreted factors from CAFs induce responses in a patient-specific fashion that may change chemosensitivity, and (2) suggest targeting epigenetic mediators in PDOs and CAFs may help sensitize tumors to chemotherapy.
 Citation Format: Emilie Jaune-Pons, Zachary Klassen, Rachel Lu, Ye Shen, Nadeem Hussain, Michael Sey, Ken Leslie, Ephraim Tang, Anton Skaro, Matthew Cecchini, Crystal Engelage, Danielle Porplycia, Stephen Welch, Brian Yan, Christopher Pin. Patient-specific differences in cancer-associated fibroblasts alter tumor organoid phenotype and chemosensitivity in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B067.

Abstract B067: Patient-specific differences in cancer-associated fibroblasts alter tumor organoid phenotype and chemosensitivity in pancreatic ductal adenocarcinoma

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Abstract B029: Epigenetic characterization of patient-derived organoids and cancer-associated fibroblasts from endoscopic ultrasound of pancreatic cancer

Comparison of Cervical Vertebral Maturation with Fishman’s Skeletal Maturity Index Method in Assessment of Growth Status

Extended delay in endoscopic mucosal resection is not associated with adverse outcomes: Findings from the COVID-19 pandemic

Abstract B067: Patient-specific differences in cancer-associated fibroblasts alter tumor organoid phenotype and chemosensitivity in pancreatic ductal adenocarcinoma