Pub Date : 2024-10-03DOI: 10.1016/j.stem.2024.07.008
Hiroaki Okae, Shun Shibata, Takahiro Arima
In this issue of Cell Stem Cell, Siriwardena et al. analyze peri- and post-implantation marmoset trophoblast development in detail and establish marmoset trophoblast stem cell (TSC) lines from pluripotent stem cells (PSCs). Comparative analysis of marmoset and human TSCs provides insights into species-specific implantation and placentation strategies.
{"title":"Common and uncommon findings in marmoset and human trophoblast stem cells","authors":"Hiroaki Okae, Shun Shibata, Takahiro Arima","doi":"10.1016/j.stem.2024.07.008","DOIUrl":"https://doi.org/10.1016/j.stem.2024.07.008","url":null,"abstract":"In this issue of <em>Cell Stem Cell</em>, Siriwardena et al. analyze peri- and post-implantation marmoset trophoblast development in detail and establish marmoset trophoblast stem cell (TSC) lines from pluripotent stem cells (PSCs). Comparative analysis of marmoset and human TSCs provides insights into species-specific implantation and placentation strategies.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"33 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1016/j.stem.2024.09.005
Thomas H. Ambrosi, Michael T. Longaker
No Abstract
无摘要
{"title":"Charles “Chuck” K.F. Chan (1975–2024)","authors":"Thomas H. Ambrosi, Michael T. Longaker","doi":"10.1016/j.stem.2024.09.005","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.005","url":null,"abstract":"No Abstract","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"25 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-03DOI: 10.1016/j.stem.2024.09.002
Marta N. Shahbazi, Vincent Pasque
The use of stem cells to model the early human embryo promises to transform our understanding of developmental biology and human reproduction. In this review, we present our current knowledge of the first 2 weeks of human embryo development. We first focus on the distinct cell lineages of the embryo and the derivation of stem cell lines. We then discuss the intercellular crosstalk that guides early embryo development and how this crosstalk is recapitulated in vitro to generate stem cell-based embryo models. We highlight advances in this fast-developing field, discuss current limitations, and provide a vision for the future.
{"title":"Early human development and stem cell-based human embryo models","authors":"Marta N. Shahbazi, Vincent Pasque","doi":"10.1016/j.stem.2024.09.002","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.002","url":null,"abstract":"The use of stem cells to model the early human embryo promises to transform our understanding of developmental biology and human reproduction. In this review, we present our current knowledge of the first 2 weeks of human embryo development. We first focus on the distinct cell lineages of the embryo and the derivation of stem cell lines. We then discuss the intercellular crosstalk that guides early embryo development and how this crosstalk is recapitulated <em>in vitro</em> to generate stem cell-based embryo models. We highlight advances in this fast-developing field, discuss current limitations, and provide a vision for the future.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"23 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3′ UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.
{"title":"Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance","authors":"Guoqiang Han, Manman Cui, Pengbo Lu, Tiantian Zhang, Rong Yin, Jin Hu, Jihua Chai, Jing Wang, Kexin Gao, Weidong Liu, Shuxin Yao, Ziyan Cao, Yanbing Zheng, Wen Tian, Rongxia Guo, Min Shen, Zheming Liu, Weiming Li, Shanshan Zhao, Xiangpeng Lin, Haojian Zhang","doi":"10.1016/j.stem.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.008","url":null,"abstract":"Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3′ UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"12 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Directed differentiation of stem cells toward chondrogenesis in vitro and in situ to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1mCherry and COL10A1eGFP double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration in situ. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.
在体外和原位引导干细胞向软骨生成方向分化以再生软骨时，会出现脱靶分化和肥大倾向。在这里，我们用携带COL2A1mCherry和COL10A1eGFP双报告基因的人类扩增多能干细胞（hEPSCs）生成了软骨类器官系统，从而实现了对软骨生成和肥大的实时监测。在筛选了 2,040 种美国 FDA 批准的药物后，我们发现α-肾上腺素能受体（α-AR）拮抗剂，尤其是酚妥拉明，能刺激软骨生成，但抑制肥大，而α2-AR 激动剂能减少软骨生成，诱导肥大。酚妥拉明能防止hEPSC软骨类器官模型和人体软骨外植体模型中的软骨退化，并刺激微骨折激活的内源性骨骼干细胞实现透明样软骨再生，而不会出现原位纤维化退化。从机理上讲，α2-AR 信号通过环磷酸鸟苷（cGMP）依赖性分泌型白细胞蛋白酶抑制剂（SLPI）的产生诱导肥大变性。SLPI缺失的软骨类器官具有抗变性能力，有利于大面积软骨缺损的愈合。最终，以α2-AR/SLPI为靶点，通过促进软骨生成和抑制肥大来实现软骨再生，是一种前景广阔、临床可行的策略。
{"title":"A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration","authors":"Xiaocui Wei, Jingyang Qiu, Ruijun Lai, Tiantian Wei, Zhijie Lin, Shijiang Huang, Yuanjun Jiang, Zhanpeng Kuang, Hao Zeng, Yan Gong, Xiaoling Xie, Jun Yang, Yue Zhang, Sheng Zhang, Zhipeng Zou, Xuefei Gao, Xiaochun Bai","doi":"10.1016/j.stem.2024.09.001","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.001","url":null,"abstract":"Directed differentiation of stem cells toward chondrogenesis <em>in vitro</em> and <em>in situ</em> to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1<sup>mCherry</sup> and COL10A1<sup>eGFP</sup> double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration <em>in situ</em>. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"40 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-30DOI: 10.1016/j.stem.2024.09.003
Rui-Jin Ji, Guo-Hua Cao, Wei-Qiang Zhao, Mu-Yao Wang, Pan Gao, Yi-Zhou Zhang, Xue-Bin Wang, Hou-Yuan Qiu, Di-Di Chen, Xiao-Han Tong, Min Duan, Hao Yin, Ying Zhang
Acute myeloid leukemia (AML) is a malignant cancer characterized by abnormal differentiation of hematopoietic stem and progenitor cells (HSPCs). While chimeric antigen receptor T (CAR-T) cell immunotherapies target AML cells, they often induce severe on-target/off-tumor toxicity by attacking normal cells expressing the same antigen. Here, we used base editors (BEs) and a prime editor (PE) to modify the epitope of CD123 on HSPCs, protecting healthy cells from CAR-T-induced cytotoxicity while maintaining their normal function. Although BE effectively edits epitopes, complex bystander products are a concern. To enhance precision, we optimized prime editing, increasing the editing efficiency from 5.9% to 78.9% in HSPCs. Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.
{"title":"Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia","authors":"Rui-Jin Ji, Guo-Hua Cao, Wei-Qiang Zhao, Mu-Yao Wang, Pan Gao, Yi-Zhou Zhang, Xue-Bin Wang, Hou-Yuan Qiu, Di-Di Chen, Xiao-Han Tong, Min Duan, Hao Yin, Ying Zhang","doi":"10.1016/j.stem.2024.09.003","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.003","url":null,"abstract":"Acute myeloid leukemia (AML) is a malignant cancer characterized by abnormal differentiation of hematopoietic stem and progenitor cells (HSPCs). While chimeric antigen receptor T (CAR-T) cell immunotherapies target AML cells, they often induce severe on-target/off-tumor toxicity by attacking normal cells expressing the same antigen. Here, we used base editors (BEs) and a prime editor (PE) to modify the epitope of CD123 on HSPCs, protecting healthy cells from CAR-T-induced cytotoxicity while maintaining their normal function. Although BE effectively edits epitopes, complex bystander products are a concern. To enhance precision, we optimized prime editing, increasing the editing efficiency from 5.9% to 78.9% in HSPCs. Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"39 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1016/j.stem.2024.09.012
Zuzana Tothova, John M. Krill-Burger, Katerina D. Popova, Catherine C. Landers, Quinlan L. Sievers, David Yudovich, Roger Belizaire, Jon C. Aster, Elizabeth A. Morgan, Aviad Tsherniak, Benjamin L. Ebert
No Abstract
无摘要
{"title":"Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia","authors":"Zuzana Tothova, John M. Krill-Burger, Katerina D. Popova, Catherine C. Landers, Quinlan L. Sievers, David Yudovich, Roger Belizaire, Jon C. Aster, Elizabeth A. Morgan, Aviad Tsherniak, Benjamin L. Ebert","doi":"10.1016/j.stem.2024.09.012","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.012","url":null,"abstract":"No Abstract","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"30 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1016/j.stem.2024.09.009
Hui Zeng, Min Guo, Ting Zhou, Lei Tan, Chi Nok Chong, Tuo Zhang, Xue Dong, Jenny Zhaoying Xiang, Albert S. Yu, Lixia Yue, Qibin Qi, Todd Evans, Johannes Graumann, Shuibing Chen
No Abstract
无摘要
{"title":"An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study- Identified Diabetes Genes and Drug Discovery","authors":"Hui Zeng, Min Guo, Ting Zhou, Lei Tan, Chi Nok Chong, Tuo Zhang, Xue Dong, Jenny Zhaoying Xiang, Albert S. Yu, Lixia Yue, Qibin Qi, Todd Evans, Johannes Graumann, Shuibing Chen","doi":"10.1016/j.stem.2024.09.009","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.009","url":null,"abstract":"No Abstract","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"10 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1016/j.stem.2024.09.004
Dylan Siriwardena, Clara Munger, Christopher Penfold, Timo N. Kohler, Antonia Weberling, Madeleine Linneberg-Agerholm, Erin Slatery, Anna L. Ellermann, Sophie Bergmann, Stephen J. Clark, Thomas M. Rawlings, Joshua M. Brickman, Wolf Reik, Jan J. Brosens, Magdalena Zernicka-Goetz, Erika Sasaki, Rüdiger Behr, Florian Hollfelder, Thorsten E. Boroviak
Early human trophoblast development has remained elusive due to the inaccessibility of the early conceptus. Non-human primate models recapitulate many features of human development and allow access to early postimplantation stages. Here, we tracked the pre- to postimplantation transition of the trophoblast lineage in superficially implanting marmoset embryos in vivo. We differentiated marmoset naive pluripotent stem cells into trophoblast stem cells (TSCs), which exhibited trophoblast-specific transcriptome, methylome, differentiation potential, and long-term self-renewal. Notably, human TSC culture conditions failed to support marmoset TSC derivation, instead inducing an extraembryonic mesoderm-like fate in marmoset cells. We show that combined MEK, TGF-β/NODAL, and histone deacetylase inhibition stabilizes a periimplantation trophoblast-like identity in marmoset TSCs. By contrast, these conditions differentiated human TSCs toward extravillous trophoblasts. Our work presents a paradigm to harness the evolutionary divergence in implantation strategies to elucidate human trophoblast development and invasion.
{"title":"Marmoset and human trophoblast stem cells differ in signaling requirements and recapitulate divergent modes of trophoblast invasion","authors":"Dylan Siriwardena, Clara Munger, Christopher Penfold, Timo N. Kohler, Antonia Weberling, Madeleine Linneberg-Agerholm, Erin Slatery, Anna L. Ellermann, Sophie Bergmann, Stephen J. Clark, Thomas M. Rawlings, Joshua M. Brickman, Wolf Reik, Jan J. Brosens, Magdalena Zernicka-Goetz, Erika Sasaki, Rüdiger Behr, Florian Hollfelder, Thorsten E. Boroviak","doi":"10.1016/j.stem.2024.09.004","DOIUrl":"https://doi.org/10.1016/j.stem.2024.09.004","url":null,"abstract":"Early human trophoblast development has remained elusive due to the inaccessibility of the early conceptus. Non-human primate models recapitulate many features of human development and allow access to early postimplantation stages. Here, we tracked the pre- to postimplantation transition of the trophoblast lineage in superficially implanting marmoset embryos <em>in vivo</em>. We differentiated marmoset naive pluripotent stem cells into trophoblast stem cells (TSCs), which exhibited trophoblast-specific transcriptome, methylome, differentiation potential, and long-term self-renewal. Notably, human TSC culture conditions failed to support marmoset TSC derivation, instead inducing an extraembryonic mesoderm-like fate in marmoset cells. We show that combined MEK, TGF-β/NODAL, and histone deacetylase inhibition stabilizes a periimplantation trophoblast-like identity in marmoset TSCs. By contrast, these conditions differentiated human TSCs toward extravillous trophoblasts. Our work presents a paradigm to harness the evolutionary divergence in implantation strategies to elucidate human trophoblast development and invasion.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142313579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-20DOI: 10.1016/j.stem.2024.08.010
Ahmad Al Shihabi, Peyton J. Tebon, Huyen Thi Lam Nguyen, Jomjit Chantharasamee, Sara Sartini, Ardalan Davarifar, Alexandra Y. Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Enrique Gonzalez, Summer Norris, Jantzen Sperry, Jonathan Nakashima, Nasrin Tavanaie, Helena Winata, Sorel T. Fitz-Gibbon, Takafumi N. Yamaguchi, Jae H. Jeong, Sarah Dry, Arun S. Singh, Alice Soragni
Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information.
{"title":"The landscape of drug sensitivity and resistance in sarcoma","authors":"Ahmad Al Shihabi, Peyton J. Tebon, Huyen Thi Lam Nguyen, Jomjit Chantharasamee, Sara Sartini, Ardalan Davarifar, Alexandra Y. Jensen, Miranda Diaz-Infante, Hannah Cox, Alfredo Enrique Gonzalez, Summer Norris, Jantzen Sperry, Jonathan Nakashima, Nasrin Tavanaie, Helena Winata, Sorel T. Fitz-Gibbon, Takafumi N. Yamaguchi, Jae H. Jeong, Sarah Dry, Arun S. Singh, Alice Soragni","doi":"10.1016/j.stem.2024.08.010","DOIUrl":"https://doi.org/10.1016/j.stem.2024.08.010","url":null,"abstract":"<p>Sarcomas are rare malignancies with over 100 distinct histological subtypes. Their rarity and heterogeneity pose significant challenges to identifying effective therapies, and approved regimens show varied responses. Novel, personalized approaches to therapy are needed to improve patient outcomes. Patient-derived tumor organoids (PDTOs) model tumor behavior across an array of malignancies. We leverage PDTOs to characterize the landscape of drug resistance and sensitivity in sarcoma, collecting 194 specimens from 126 patients spanning 24 distinct sarcoma subtypes. Our high-throughput organoid screening pipeline tested single agents and combinations, with results available within a week from surgery. Drug sensitivity correlated with clinical features such as tumor subtype, treatment history, and disease trajectory. PDTO screening can facilitate optimal drug selection and mirror patient outcomes in sarcoma. We could identify at least one FDA-approved or NCCN-recommended effective regimen for 59% of the specimens, demonstrating the potential of our pipeline to provide actionable treatment information.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"5 1","pages":""},"PeriodicalIF":23.9,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142246740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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