HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line
IntroductionMedullary pancreatic carcinoma (MPC) is a rare subtype of pancreatic ductal adenocarcinoma. MPCs represent less than 1% of all pancreatic cancers, and, with only 26 cases in the literature, knowledge regarding drug response and treatment outcome is very limited.Material and methodsWe pre...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1082927/full |
| _version_ | 1797944716217548800 |
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| author | Jens von den Driesch Jana Flöttmann Friedrich Prall Christina S. Mullins Michael Linnebacher Florian Bürtin |
| author_facet | Jens von den Driesch Jana Flöttmann Friedrich Prall Christina S. Mullins Michael Linnebacher Florian Bürtin |
| author_sort | Jens von den Driesch |
| collection | DOAJ |
| description | IntroductionMedullary pancreatic carcinoma (MPC) is a rare subtype of pancreatic ductal adenocarcinoma. MPCs represent less than 1% of all pancreatic cancers, and, with only 26 cases in the literature, knowledge regarding drug response and treatment outcome is very limited.Material and methodsWe present the case of a 64-year-old male patient with MPC who was treated by left pancreatic resection and adjuvant chemotherapy. Due to local recurrence, the patient underwent intended curative reoperation. From both surgical specimens, patient-derived xenografts (PDXs) and, from the recurrence, a patient-derived cell line (PDCL) were established. We subsequently performed an in-depth characterization of this cell line including phenotypic characterization, surface protein expression, growth, and migratory performance as well as mutational analysis using whole-exome sequencing (WES). Additionally, in vitro drug sensitivity toward the standard-of-care chemotherapeutic regimen and selected targeted therapies was evaluated.ResultsThe pathological and molecular properties of this rare MPC case observed in the patient’s tumors are preserved in the corresponding PDX and the PDCL of HROP68Tu2. Despite displaying an “immunogenic phenotype” with marked T-cell infiltration and a high-level expression of HLA II and Programmed death-ligand 1 (PD-L1), molecular analysis revealed microsatellite stability but a multitude of mutations affecting KRAS, TP53, KAT6B, FOXG1, RUNX1, and GRIK2 among others. Furthermore, HROP68Tu2 cells were susceptible toward 5-FU, irinotecan, oxaliplatin, gemcitabine, paclitaxel, and erlotinib as single agents, but only a moderate synergistic response was seen to the drugs of the FOLFIRINOX regimen. Even worse, the drugs of the two combinations gemcitabine plus paclitaxel and gemcitabine plus erlotinib showed antagonistic effects. Moreover, lapatinib, PRIMA-Met1, and olaparib selected as targeted therapeutics according to the mutational profiles and protein expression inhibited HROP68Tu2 cells’ growth.ConclusionThis study illustrates the establishment of the first preclinical MPC models as well as the first in-depth characterization of an MPC PDCL. Since the scientific and clinical knowledge of this rare pancreatic cancer type is very limited, the presented models contribute to a better understanding of MPC and might be a valuable tool for the development of future treatment options. |
| first_indexed | 2024-04-10T20:43:59Z |
| format | Article |
| id | doaj.art-b6fd84eef22e4da4a31b7a57d46101fa |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T20:43:59Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-b6fd84eef22e4da4a31b7a57d46101fa2023-01-24T14:58:21ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-01-011210.3389/fonc.2022.10829271082927HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell lineJens von den Driesch0Jana Flöttmann1Friedrich Prall2Christina S. Mullins3Michael Linnebacher4Florian Bürtin5Clinic of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, University of Rostock, Rostock, GermanyClinic of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, University of Rostock, Rostock, GermanyInstitute of Pathology, University Medical Center Rostock, University of Rostock, Rostock, GermanyClinic of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, University of Rostock, Rostock, GermanyClinic of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, University of Rostock, Rostock, GermanyClinic of General, Visceral, Vascular and Transplantation Surgery, University Medical Center Rostock, University of Rostock, Rostock, GermanyIntroductionMedullary pancreatic carcinoma (MPC) is a rare subtype of pancreatic ductal adenocarcinoma. MPCs represent less than 1% of all pancreatic cancers, and, with only 26 cases in the literature, knowledge regarding drug response and treatment outcome is very limited.Material and methodsWe present the case of a 64-year-old male patient with MPC who was treated by left pancreatic resection and adjuvant chemotherapy. Due to local recurrence, the patient underwent intended curative reoperation. From both surgical specimens, patient-derived xenografts (PDXs) and, from the recurrence, a patient-derived cell line (PDCL) were established. We subsequently performed an in-depth characterization of this cell line including phenotypic characterization, surface protein expression, growth, and migratory performance as well as mutational analysis using whole-exome sequencing (WES). Additionally, in vitro drug sensitivity toward the standard-of-care chemotherapeutic regimen and selected targeted therapies was evaluated.ResultsThe pathological and molecular properties of this rare MPC case observed in the patient’s tumors are preserved in the corresponding PDX and the PDCL of HROP68Tu2. Despite displaying an “immunogenic phenotype” with marked T-cell infiltration and a high-level expression of HLA II and Programmed death-ligand 1 (PD-L1), molecular analysis revealed microsatellite stability but a multitude of mutations affecting KRAS, TP53, KAT6B, FOXG1, RUNX1, and GRIK2 among others. Furthermore, HROP68Tu2 cells were susceptible toward 5-FU, irinotecan, oxaliplatin, gemcitabine, paclitaxel, and erlotinib as single agents, but only a moderate synergistic response was seen to the drugs of the FOLFIRINOX regimen. Even worse, the drugs of the two combinations gemcitabine plus paclitaxel and gemcitabine plus erlotinib showed antagonistic effects. Moreover, lapatinib, PRIMA-Met1, and olaparib selected as targeted therapeutics according to the mutational profiles and protein expression inhibited HROP68Tu2 cells’ growth.ConclusionThis study illustrates the establishment of the first preclinical MPC models as well as the first in-depth characterization of an MPC PDCL. Since the scientific and clinical knowledge of this rare pancreatic cancer type is very limited, the presented models contribute to a better understanding of MPC and might be a valuable tool for the development of future treatment options.https://www.frontiersin.org/articles/10.3389/fonc.2022.1082927/fullPDAC - pancreatic ductal adenocarcinomarare malignancymedullary adenocarcinomaprecision medicinepatient-derived cell line |
| spellingShingle | Jens von den Driesch Jana Flöttmann Friedrich Prall Christina S. Mullins Michael Linnebacher Florian Bürtin HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line Frontiers in Oncology PDAC - pancreatic ductal adenocarcinoma rare malignancy medullary adenocarcinoma precision medicine patient-derived cell line |
| title | HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line |
| title_full | HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line |
| title_fullStr | HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line |
| title_full_unstemmed | HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line |
| title_short | HROP68: A rare case of medullary pancreatic cancer—characterization and chemosensitivity of the first patient-derived cell line |
| title_sort | hrop68 a rare case of medullary pancreatic cancer characterization and chemosensitivity of the first patient derived cell line |
| topic | PDAC - pancreatic ductal adenocarcinoma rare malignancy medullary adenocarcinoma precision medicine patient-derived cell line |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1082927/full |
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