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Cancer Research and Treatment Oct 2023Patient-derived tumor cells can be a powerful resource for studying pathophysiological mechanisms and developing robust strategies for precision medicine. However,...
PURPOSE
Patient-derived tumor cells can be a powerful resource for studying pathophysiological mechanisms and developing robust strategies for precision medicine. However, establishing organoids from patient-derived cells is challenging because of limited access to tissue specimens. Therefore, we aimed to establish organoids from malignant ascites and pleural effusions.
MATERIALS AND METHODS
Ascitic or pleural fluid from pancreatic, gastric, and breast cancer patients was collected and concentrated to culture tumor cells ex vivo. Organoids were considered to be successfully cultured when maintained for five or more passages. Immunohistochemical staining was performed to compare the molecular features, and drug sensitivity was assayed to analyze the clinical responses of original patients.
RESULTS
We collected 70 fluid samples from 58 patients (pancreatic cancer, n=39; gastric cancer, n=21; and breast cancer, n=10). The overall success rate was 40%; however, it differed with types of malignancy, with pancreatic, gastric, and breast cancers showing 48.7%, 33.3%, and 20%, respectively. Cytopathological results significantly differed between successful and failed cases (p=0.014). Immunohistochemical staining of breast cancer organoids showed molecular features identical to those of tumor tissues. In drug sensitivity assays, pancreatic cancer organoids recapitulated the clinical responses of the original patients.
CONCLUSION
Tumor organoids established from malignant ascites or pleural effusion of pancreatic, gastric, and breast cancers reflect the molecular characteristics and drug sensitivity profiles. Our organoid platform could be used as a testbed for patients with pleural and peritoneal metastases to guide precision oncology and drug discovery.
Topics: Humans; Female; Ascites; Precision Medicine; Pancreatic Neoplasms; Breast Neoplasms; Peritoneal Neoplasms; Organoids
PubMed: 37309112
DOI: 10.4143/crt.2022.1630 -
Cell Reports. Medicine Mar 2024Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes...
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer, and novel treatment regimens are direly needed. Epigenetic regulation contributes to the development of various cancer types, but its role in the development of and potential as a therapeutic target for PDAC remains underexplored. Here, we show that PRMT1 is highly expressed in murine and human pancreatic cancer and is essential for cancer cell proliferation and tumorigenesis. Deletion of PRMT1 delays pancreatic cancer development in a KRAS-dependent mouse model, and multi-omics analyses reveal that PRMT1 depletion leads to global changes in chromatin accessibility and transcription, resulting in reduced glycolysis and a decrease in tumorigenic capacity. Pharmacological inhibition of PRMT1 in combination with gemcitabine has a synergistic effect on pancreatic tumor growth in vitro and in vivo. Collectively, our findings implicate PRMT1 as a key regulator of pancreatic cancer development and a promising target for combination therapy.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Epigenesis, Genetic; Gemcitabine; Pancreatic Neoplasms; Protein-Arginine N-Methyltransferases; Repressor Proteins
PubMed: 38460517
DOI: 10.1016/j.xcrm.2024.101461 -
The Journal of Clinical Endocrinology... Mar 2024Insulinomas are hormone-producing pancreatic neuroendocrine neoplasms with an estimated incidence of 1 to 4 cases per million per year. Extrapancreatic insulinomas are...
Insulinomas are hormone-producing pancreatic neuroendocrine neoplasms with an estimated incidence of 1 to 4 cases per million per year. Extrapancreatic insulinomas are extremely rare. Most insulinomas present with the Whipple triad: (1) symptoms, signs, or both consistent with hypoglycemia; (2) a low plasma glucose measured at the time of the symptoms and signs; and (3) relief of symptoms and signs when the glucose is raised to normal. Nonmetastatic insulinomas are nowadays referred to as "indolent" and metastatic insulinomas as "aggressive." The 5-year survival of patients with an indolent insulinoma has been reported to be 94% to 100%; for patients with an aggressive insulinoma, this amounts to 24% to 67%. Five percent to 10% of insulinomas are associated with the multiple endocrine neoplasia type 1 syndrome. Localization of the insulinoma and exclusion or confirmation of metastatic disease by computed tomography is followed by endoscopic ultrasound or magnetic resonance imaging for indolent, localized insulinomas. Glucagon-like peptide 1 receptor positron emission tomography/computed tomography or positron emission tomography/magnetic resonance imaging is a highly sensitive localization technique for seemingly occult, indolent, localized insulinomas. Supportive measures and somatostatin receptor ligands can be used for to control hypoglycemia. For single solitary insulinomas, curative surgical excision remains the treatment of choice. In aggressive malignant cases, debulking procedures, somatostatin receptor ligands, peptide receptor radionuclide therapy, everolimus, sunitinib, and cytotoxic chemotherapy can be valuable options.
Topics: Humans; Insulinoma; Receptors, Somatostatin; Pancreatic Neoplasms; Hypoglycemia; Neuroendocrine Tumors
PubMed: 37925662
DOI: 10.1210/clinem/dgad641 -
Cells Oct 2023Pancreatic cancer is characterized by a poor prognosis, with its five-year survival rate lower than that of any other cancer type. Gemcitabine, a standard treatment for...
Pancreatic cancer is characterized by a poor prognosis, with its five-year survival rate lower than that of any other cancer type. Gemcitabine, a standard treatment for pancreatic cancer, often has poor outcomes for patients as a result of chemoresistance. Therefore, novel therapeutic targets must be identified to overcome gemcitabine resistance. Here, we found that SLC38A5, a glutamine transporter, is more highly overexpressed in gemcitabine-resistant patients than in gemcitabine-sensitive patients. Furthermore, the deletion of SLC38A5 decreased the proliferation and migration of gemcitabine-resistant PDAC cells. We also found that the inhibition of SLC38A5 triggered the ferroptosis signaling pathway via RNA sequencing. Also, silencing SLC38A5 induced mitochondrial dysfunction and reduced glutamine uptake and glutathione (GSH) levels, and downregulated the expressions of GSH-related genes NRF2 and GPX4. The blockade of glutamine uptake negatively modulated the mTOR-SREBP1-SCD1 signaling pathway. Therefore, suppression of SLC38A5 triggers ferroptosis via two pathways that regulate lipid ROS levels. Similarly, we observed that knockdown of SLC38A5 restored gemcitabine sensitivity by hindering tumor growth and metastasis in the orthotopic mouse model. Altogether, our results demonstrate that SLC38A5 could be a novel target to overcome gemcitabine resistance in PDAC therapy.
Topics: Animals; Mice; Humans; Gemcitabine; Deoxycytidine; Ferroptosis; Glutamine; Drug Resistance, Neoplasm; Cell Line, Tumor; Pancreatic Neoplasms; Amino Acid Transport Systems, Neutral
PubMed: 37887353
DOI: 10.3390/cells12202509 -
Scientific Reports Oct 2023The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a...
The existing biomarkers are insufficient for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary mucinous neoplasm (IPMN) is a precursor to PDAC; therefore, identifying biomarkers from differentially expressed genes (DEGs) of PDAC and IPMN is a new and reliable strategy for predicting the prognosis of PDAC. In this study, four datasets were downloaded from the Gene Expression Omnibus database and standardized using the R package 'limma.' A total of 51 IPMN and 81 PDAC samples were analyzed, and 341 DEGs in PDAC and IPMN were identified; DEGs were involved in the extracellular matrix and tumor microenvironment. An acceptable survival prognosis was demonstrated by SDC1 and ITGA2, which were highly expressed during in vitro PDAC cell proliferation, apoptosis, and migration. SDC1 was enriched in interferon alpha (IFN-α) response and ITGA2 was primarily detected in epithelial-mesenchymal transition (EMT), which was verified using western blotting. We concluded that SDC1 and ITGA2 are potential prognostic biomarkers for PDAC associated with IPMN. Downregulation of SDC1 and ITGA2 expression in PDAC occurs via a mechanism involving possible regulation of IFN-α response, EMT, and immunity, which may act as new targets for PDAC therapy.
Topics: Humans; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; Pancreatic Neoplasms; Prognosis; Syndecan-1; Tumor Microenvironment
PubMed: 37907515
DOI: 10.1038/s41598-023-44646-x -
Abdominal Radiology (New York) Aug 2023This study aimed to characterize the clinical and imaging findings of intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) compared to those of intraductal...
PURPOSE
This study aimed to characterize the clinical and imaging findings of intraductal oncocytic papillary neoplasm of the pancreas (IOPN-P) compared to those of intraductal papillary mucinous adenoma/carcinoma (IPMA/IPMC).
METHODS
This multi-institutional retrospective study reviewed the clinical, imaging, and pathological findings of 21 patients with pathologically proven IOPN-P. Twenty-one computed tomography (CT) and magnetic resonance imaging, and seven F-fluorodeoxyglucose (FDG)-positron emission tomography were performed before surgery. The following findings were evaluated: preoperative blood test results, lesion size and location, pancreatic duct diameter, contrast-enhancement effect, bile duct and peripancreatic invasion, maximum standardized uptake (SUVmax) value, and pathological stromal invasion.
RESULTS
Serum carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA19-9) levels were significantly higher in the IPMN/IPMC group than in the IOPN-P group. Except in one patient, IOPN-P showed multifocal cystic lesions with solid components or a tumor in the main pancreatic duct (MPD) with dilatation. IOPN-P had a higher frequency of solid parts and a lower frequency of downstream MPD dilatation than IPMA. IPMC showed smaller overall cyst size, more radiological peripancreatic invasion, and worse recurrence-free and overall survival than IOPN-P. The average SUVmax value of IOPN-P was 7.5. Pathologically, 17 of the 21 IOPN-Ps had a malignant component, and six showed stromal invasion.
CONCLUSION
IOPN-P shows cystic-solid lesions similar to IPMC but has lower serum CEA and CA19-9 levels, larger overall cyst size, lower frequency of peripancreatic invasion, and more favorable prognosis than IPMC. Moreover, the high FDG uptake by IOPN-Ps may be a characteristic finding of this study.
Topics: Humans; Carcinoma, Pancreatic Ductal; Retrospective Studies; Fluorodeoxyglucose F18; Carcinoembryonic Antigen; CA-19-9 Antigen; Pancreatic Neoplasms; Pancreas; Cysts; Neoplasm Invasiveness
PubMed: 37358603
DOI: 10.1007/s00261-023-03985-z -
Modern Pathology : An Official Journal... Sep 2023Early detection and treatment of invasive carcinoma arising in association with intraductal papillary mucinous neoplasm (IPMN), which is biologically and...
Early detection and treatment of invasive carcinoma arising in association with intraductal papillary mucinous neoplasm (IPMN), which is biologically and (epi)genetically distinct from conventional pancreatic ductal adenocarcinoma, provide an opportunity to improve the prognosis of this lethal disease. Despite the successful application of programmed death (ligand) 1 (PD-[L]1)-blocking strategies in numerous cancers, the immune microenvironment of IPMN with associated invasive carcinoma remains elusive. Here, we investigated CD8 T cells, CD68 macrophages, PD-L1, and V-domain immunoglobulin suppressor of T-cell activation (VISTA) in 60 patients with IPMN with associated invasive carcinoma using immunohistochemistry, explored their correlations with clinicopathologic variables and prognosis, and compared them with those in 76 patients with IPMN without invasive carcinoma (60 low-grade and 16 high-grade lesions). Using antibodies against CD8, CD68, and VISTA, we evaluated tumor-infiltrating immune cells in 5 high-power fields (×400) and calculated the corresponding mean counts. PD-L1 with a combined positive score of ≥1 was regarded as positive, and VISTA expression on tumor cells (TCs) was deemed positive when ≥1% of TCs showed membranous/cytoplasmic staining. A reduction of CD8 T cells and an increase of macrophages were observed during carcinogenesis. Positive PD-L1 combined positive score and VISTA expression on TCs were 13% and 11% in the intraductal component of IPMN with associated invasive carcinoma, 15% and 12% in the associated invasive carcinoma, and 6% and 4% in IPMN without an invasive carcinoma, respectively. Interestingly, the PD-L1 positivity rate was the highest in a subset of associated invasive carcinomas (predominantly gastric-type-derived) and was associated with higher counts of CD8 T cells, macrophages, and VISTA immune cells. Accumulation of VISTA immune cells was observed in the intraductal component of IPMN with associated invasive carcinoma compared with that of low-grade IPMN, whereas in intestinal-type IPMN with associated invasive carcinoma, the number of these cells decreased during the transition from the intraductal component to the associated invasive carcinoma. Survival analysis revealed that a higher number of macrophages predicted poorer prognosis. In conclusion, our results might help in individualized immunotherapeutic strategies for these patients.
Topics: Humans; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Pancreatic Intraductal Neoplasms; Adenocarcinoma, Mucinous; Pancreatic Neoplasms; Pancreas; Carcinoma, Pancreatic Ductal; Neoplasm Invasiveness; Tumor Microenvironment
PubMed: 37244388
DOI: 10.1016/j.modpat.2023.100223 -
Turkish Journal of Medical Sciences 2023Long noncoding RNAs (lncRNAs) are noncoding RNA molecules with a heterogeneous structure consisting of 200 or more nucleotides. Because these noncoding RNAs are... (Review)
Review
Long noncoding RNAs (lncRNAs) are noncoding RNA molecules with a heterogeneous structure consisting of 200 or more nucleotides. Because these noncoding RNAs are transcribed by RNA polymerase II, they have properties similar to messenger RNA (mRNA). Contrary to popular belief, the term "ncRNA" originated before the discovery of microRNAs. LncRNA genes are more numerous than protein-coding genes. They are the focus of current molecular research because of their pivotal roles in cancer-related processes such as cell proliferation, differentiation, and migration. The incidence of pancreatic cancer (PC) is increasing around the world and research on the molecular aspects of PC are growing. In this review, it is aimed to provide critical information about lncRNAs in PC, including the biological and oncological behaviors of lncRNAs in PC and their potential application in therapeutic strategies and as diagnostic tumor markers.
Topics: Humans; RNA, Long Noncoding; Pancreatic Neoplasms; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38813489
DOI: 10.55730/1300-0144.5724 -
Acta Medica Portuguesa Oct 2023Pancreatic duct adenocarcinoma is currently the sixth-leading cause of cancer death worldwide and the fourth in Europe, with a continuous increase in annual lethality in... (Review)
Review
Pancreatic duct adenocarcinoma is currently the sixth-leading cause of cancer death worldwide and the fourth in Europe, with a continuous increase in annual lethality in Portugal during the last two decades. Surgical en-bloc resection of the tumor with microscopic-negative margins and an adequate lymphadenectomy is the only possibility of long-term survival. As this type of cancer is a systemic disease, there is a high rate of recurrence even after curative resection, turning systemic therapy the core of its management, mostly based on chemotherapy. Neoadjuvant strategies for nonmetastatic disease showed significant improvement in overall survival compared with upfront surgery, namely in borderline resectable disease. Moreover, these strategies provided downstaging in several situations allowing R0 resections. Under these new oncologic strategies, several recent surgical issues were introduced, namely more aggressive vascular resections and even tumor resections in oligometastatic disease. This review revisits the state-of-the-art of surgical and oncological interventions in pancreatic duct adenocarcinoma and highlights recent advances in the field aiming to achieve higher survival rates.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Neoadjuvant Therapy; Europe
PubMed: 37788655
DOI: 10.20344/amp.19957 -
Journal of Proteome Research Dec 2023Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has...
Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRAS mutant proteins, which is one of the main drivers of pancreatic cancer. To better understand the mechanism of action of this compound, I performed both proteomics and metabolomics on four KRAS mutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single-cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1498 single cells were analyzed. From these cells, 3140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Proteomics; Pancreatic Neoplasms; Mutation
PubMed: 37983312
DOI: 10.1021/acs.jproteome.3c00212