Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites 公告 2023-12-11 14:53:03 Written By Kym Kilbourne Title: Druggable growth dependencies and tumor evoution analysis in patient-dereived organoids of neuroendocrine neoplasms from multiple body sites Research Background and Significance Neuroendocrine tumors (NENs) encompass both benign neuroendocrine tumors (NETs) and malignant neuroendocrine carcinomas (NECs), with limited treatment options, partly due to the scarcity of accurate models to study these tumors. NENs are most prevalent in the lung and gastroenteropancreatic (GEP) systems, particularly small cell neuroendocrine carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). LCNEC is a highly differentiated, low-grade tumor with poor clinical prognosis and a survival period typically less than one year. Although there is relatively more research on small cell carcinomas, the study of LCNEC and NETs is hindered by the lack of preclinical models. Establishing patient-derived tumor organoids (PDTOs) is crucial for studying the biology and therapeutic targets of NENs. Through these models, researchers can better understand the evolution process, tumor heterogeneity, and drug sensitivity of tumors. The significance of this study lies in revealing the biological characteristics of NEN PDTOs from different sites, providing a foundation for the development of new treatment strategies. Research Introduction This study, conducted by Talya L. Dayton and colleagues, established patient-derived tumor organoids (PDTOs) from neuroendocrine tumors (NETs and LCNECs) of various sites. The study demonstrated through multi-omics molecular analysis that PDTOs maintain the gene expression patterns, tumor heterogeneity, and evolution processes of their parental tumors. Drug sensitivity analysis revealed EGF dependency and ASCL1 as potential biomarkers for therapeutic vulnerability. Research Highlights Established PDTOs from NETs and LCNECs of various sites, successfully maintaining the biological characteristics of the tumors. PDTOs can reproduce the tumor heterogeneity and evolution processes of the parental tumors, providing a model for studying tumor evolution. Drug sensitivity analysis revealed EGF dependency, indicating that the dependency of some pulmonary NETs on EGF may be a therapeutic vulnerability. Identified ASCL1 as a potential biomarker for LCNEC response to BCL-2 inhibitors, emphasizing the importance of PDTO models in identifying therapeutic targets. Research Results Establishment of Patient-Derived Tumor Organoids (PDTOs): The research team successfully established PDTO models from neuroendocrine tumors (NETs and LCNECs) of various sites, including 11 pulmonary NETs and 6 LCNECs. These PDTOs can be cultured in vitro for long periods, showing good growth characteristics. The study also established short-term cultured small intestine NET (SINET) PDTOs, which, although unable to extend long-term in vitro, provided a new model for studying small intestine NETs. Tumor Heterogeneity and Evolution Reproduction: Through histological analysis, the study showed that PDTOs can retain the histological characteristics of their parental tumors, including the expression of neuroendocrine markers (such as CHGA, SYP, and CD56/NCAM1), which are similar in expression between PDTOs and their parental tumors. Immunohistochemistry (IHC) staining showed that the proliferation index (the proportion of Ki67-positive cells) of PDTOs is similar to that of their parental tumors, indicating that PDTOs can effectively simulate the biological characteristics of tumors. Gene Expression Pattern Maintenance: Through whole-genome sequencing (WGS) and RNA sequencing (RNA-seq), the study found that PDTOs maintain gene expression patterns similar to their parental tumors, especially in the expression of neuroendocrine markers and transcription factors (such as ASCL1, INSM1, and NEUROD1). This indicates that PDTOs are not only morphologically similar to parental tumors but also maintain molecular characteristics, which can be used to study tumor biology and drug response. Tumor Mutational Burden (TMB): The study showed that the mutational burden of PDTOs is similar to that of their parental tumors, with low-grade NETs having a lower mutational burden (average 1.26) and LCNECs having a higher mutational burden (average 11.5). In high-purity PDTOs, the same mutations observed in the parental tumors were found, demonstrating the genetic consistency of PDTOs. Drug Sensitivity Testing: The research team conducted drug sensitivity testing on 5 LCNEC PDTOs and found differences in drug responses among different PDTOs, such as paclitaxel and mTOR inhibitor everolimus. In particular, the sensitivity of LNET10 PDTO to BRAF and MEK inhibitors was confirmed, related to its BRAF V600E mutation, indicating that this mutation may be a potential therapeutic target. EGF Dependency: The study found that some pulmonary NET PDTOs exhibit dependency on epidermal growth factor (EGF). In the presence of EGF, the growth of these PDTOs was significantly better than under EGF-deprived culture conditions. Through immunohistochemical analysis, the study confirmed the expression of EGFR in most pulmonary NETs, with about 50% of tumors showing EGFR positivity. Research Significance The PDTO models in this study provide an important tool for studying the biology and therapeutic targets of NENs, helping to understand tumor evolution and heterogeneity. The discovery of EGF dependency offers a viable therapeutic target for pulmonary NETs, potentially providing new treatment options for patients. The identification of ASCL1 as a biomarker may help predict the response of LCNEC to BCL-2 inhibitors, emphasizing the importance of personalized therapy. The research results provide a foundation for future clinical trials and treatment strategies, especially in targeted therapy and drug development for NENs. Paper Link https://pubmed.ncbi.nlm.nih.gov/38086335/ Kym Kilbourne
Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites 公告 2023-12-11 14:53:03 Written By Kym Kilbourne Title: Druggable growth dependencies and tumor evoution analysis in patient-dereived organoids of neuroendocrine neoplasms from multiple body sites Research Background and Significance Neuroendocrine tumors (NENs) encompass both benign neuroendocrine tumors (NETs) and malignant neuroendocrine carcinomas (NECs), with limited treatment options, partly due to the scarcity of accurate models to study these tumors. NENs are most prevalent in the lung and gastroenteropancreatic (GEP) systems, particularly small cell neuroendocrine carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). LCNEC is a highly differentiated, low-grade tumor with poor clinical prognosis and a survival period typically less than one year. Although there is relatively more research on small cell carcinomas, the study of LCNEC and NETs is hindered by the lack of preclinical models. Establishing patient-derived tumor organoids (PDTOs) is crucial for studying the biology and therapeutic targets of NENs. Through these models, researchers can better understand the evolution process, tumor heterogeneity, and drug sensitivity of tumors. The significance of this study lies in revealing the biological characteristics of NEN PDTOs from different sites, providing a foundation for the development of new treatment strategies. Research Introduction This study, conducted by Talya L. Dayton and colleagues, established patient-derived tumor organoids (PDTOs) from neuroendocrine tumors (NETs and LCNECs) of various sites. The study demonstrated through multi-omics molecular analysis that PDTOs maintain the gene expression patterns, tumor heterogeneity, and evolution processes of their parental tumors. Drug sensitivity analysis revealed EGF dependency and ASCL1 as potential biomarkers for therapeutic vulnerability. Research Highlights Established PDTOs from NETs and LCNECs of various sites, successfully maintaining the biological characteristics of the tumors. PDTOs can reproduce the tumor heterogeneity and evolution processes of the parental tumors, providing a model for studying tumor evolution. Drug sensitivity analysis revealed EGF dependency, indicating that the dependency of some pulmonary NETs on EGF may be a therapeutic vulnerability. Identified ASCL1 as a potential biomarker for LCNEC response to BCL-2 inhibitors, emphasizing the importance of PDTO models in identifying therapeutic targets. Research Results Establishment of Patient-Derived Tumor Organoids (PDTOs): The research team successfully established PDTO models from neuroendocrine tumors (NETs and LCNECs) of various sites, including 11 pulmonary NETs and 6 LCNECs. These PDTOs can be cultured in vitro for long periods, showing good growth characteristics. The study also established short-term cultured small intestine NET (SINET) PDTOs, which, although unable to extend long-term in vitro, provided a new model for studying small intestine NETs. Tumor Heterogeneity and Evolution Reproduction: Through histological analysis, the study showed that PDTOs can retain the histological characteristics of their parental tumors, including the expression of neuroendocrine markers (such as CHGA, SYP, and CD56/NCAM1), which are similar in expression between PDTOs and their parental tumors. Immunohistochemistry (IHC) staining showed that the proliferation index (the proportion of Ki67-positive cells) of PDTOs is similar to that of their parental tumors, indicating that PDTOs can effectively simulate the biological characteristics of tumors. Gene Expression Pattern Maintenance: Through whole-genome sequencing (WGS) and RNA sequencing (RNA-seq), the study found that PDTOs maintain gene expression patterns similar to their parental tumors, especially in the expression of neuroendocrine markers and transcription factors (such as ASCL1, INSM1, and NEUROD1). This indicates that PDTOs are not only morphologically similar to parental tumors but also maintain molecular characteristics, which can be used to study tumor biology and drug response. Tumor Mutational Burden (TMB): The study showed that the mutational burden of PDTOs is similar to that of their parental tumors, with low-grade NETs having a lower mutational burden (average 1.26) and LCNECs having a higher mutational burden (average 11.5). In high-purity PDTOs, the same mutations observed in the parental tumors were found, demonstrating the genetic consistency of PDTOs. Drug Sensitivity Testing: The research team conducted drug sensitivity testing on 5 LCNEC PDTOs and found differences in drug responses among different PDTOs, such as paclitaxel and mTOR inhibitor everolimus. In particular, the sensitivity of LNET10 PDTO to BRAF and MEK inhibitors was confirmed, related to its BRAF V600E mutation, indicating that this mutation may be a potential therapeutic target. EGF Dependency: The study found that some pulmonary NET PDTOs exhibit dependency on epidermal growth factor (EGF). In the presence of EGF, the growth of these PDTOs was significantly better than under EGF-deprived culture conditions. Through immunohistochemical analysis, the study confirmed the expression of EGFR in most pulmonary NETs, with about 50% of tumors showing EGFR positivity. Research Significance The PDTO models in this study provide an important tool for studying the biology and therapeutic targets of NENs, helping to understand tumor evolution and heterogeneity. The discovery of EGF dependency offers a viable therapeutic target for pulmonary NETs, potentially providing new treatment options for patients. The identification of ASCL1 as a biomarker may help predict the response of LCNEC to BCL-2 inhibitors, emphasizing the importance of personalized therapy. The research results provide a foundation for future clinical trials and treatment strategies, especially in targeted therapy and drug development for NENs. Paper Link https://pubmed.ncbi.nlm.nih.gov/38086335/ Kym Kilbourne
