Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinoma
ObjectiveGastric cancer (GC) remains a leading cause of cancer-related mortality, with poorly cohesive carcinoma (PCC) exhibiting rising incidence and poor therapeutic responses. In this study, we constructed a panel of patient-derived organoids of GC and used them to understand histological accurac...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2025.1631168/full |
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| author | Yi Yin Yi Yin Shuhong Zeng Shuhong Zeng Shuhong Zeng Hui Zhang Hui Zhang Shuangshuang Wang Fei Ke Qiang Rui Jinyong Zhou Yuwen Zhuang Weixing Shen Weixing Shen Jun Qian Jun Qian Shenlin Liu Shenlin Liu |
| author_facet | Yi Yin Yi Yin Shuhong Zeng Shuhong Zeng Shuhong Zeng Hui Zhang Hui Zhang Shuangshuang Wang Fei Ke Qiang Rui Jinyong Zhou Yuwen Zhuang Weixing Shen Weixing Shen Jun Qian Jun Qian Shenlin Liu Shenlin Liu |
| author_sort | Yi Yin |
| collection | DOAJ |
| description | ObjectiveGastric cancer (GC) remains a leading cause of cancer-related mortality, with poorly cohesive carcinoma (PCC) exhibiting rising incidence and poor therapeutic responses. In this study, we constructed a panel of patient-derived organoids of GC and used them to understand histological accuracy and sensitivity profiles as well as the influence of microenvironment on these special GC subtypes.MethodsA total of 23 patient-derived GC organoid models including 12 PCC and 11 non-poorly cohesive carcinoma (NPCC) were established. Histopathological and genetic fidelity to primary tumors was validated using immunohistochemistry (IHC), immunofluorescence (IF), and H&E staining. Relative growth kinetics between PCC and NPCC organoids were measured and compared. Sizes of subcutaneously xenografted tumors harbored by mice representing different types of GC organoids were analyzed. We further examined drug sensitivities between docetaxel, 5-fuorouracil (5-FU), oxaliplatin, and irinotecan against our collected samples of patient-derived organoids. The impact of cancer-associated fibroblasts (CAFs) on organoid growth and chemoresistance was analyzed via co-culture experiments.ResultsOrganoids retained genetic and histopathological features of primary tumors. PCC-derived organoids displayed rapid growth characteristics in vitro and produced more rapidly growing tumors in vivo than NPCC. PCC organoids showed heightened sensitivity to docetaxel with lower IC50, but no significant differences were observed for 5-FU, oxaliplatin, or irinotecan. CAF co-culture enhanced organoid proliferation and conferred resistance to all tested chemotherapeutic agents.ConclusionPatient-derived GC organoids especially PCC subtypes reliably recapitulate the complexity of solid-tumors heterogeneity, predict drug responses, and elucidate stromal contributions to therapy resistance. This model could be used to develop tailoring treatments and improve personalization of therapy for clinical management of PCC. |
| format | Article |
| id | doaj-art-69dcabb969934ad49c7590891b685da9 |
| institution | Kabale University |
| issn | 2296-889X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Molecular Biosciences |
| spelling | doaj-art-69dcabb969934ad49c7590891b685da92025-08-20T03:32:17ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2025-06-011210.3389/fmolb.2025.16311681631168Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinomaYi Yin0Yi Yin1Shuhong Zeng2Shuhong Zeng3Shuhong Zeng4Hui Zhang5Hui Zhang6Shuangshuang Wang7Fei Ke8Qiang Rui9Jinyong Zhou10Yuwen Zhuang11Weixing Shen12Weixing Shen13Jun Qian14Jun Qian15Shenlin Liu16Shenlin Liu17Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaNo. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaNo. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of Chinese Medicine, Affiliated Changshu Hospital of Nantong University, Changshu No.2 People’s Hospital, Changshu, Jiangsu, ChinaDepartment of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaNo. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaCentral Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaNo. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaJiangsu Collaborative Innovation Center of Traditional Chinese Medicine Prevention and Treatment of Tumor, Nanjing, Jiangsu, ChinaDepartment of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaNo. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaDepartment of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, ChinaNo. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, ChinaObjectiveGastric cancer (GC) remains a leading cause of cancer-related mortality, with poorly cohesive carcinoma (PCC) exhibiting rising incidence and poor therapeutic responses. In this study, we constructed a panel of patient-derived organoids of GC and used them to understand histological accuracy and sensitivity profiles as well as the influence of microenvironment on these special GC subtypes.MethodsA total of 23 patient-derived GC organoid models including 12 PCC and 11 non-poorly cohesive carcinoma (NPCC) were established. Histopathological and genetic fidelity to primary tumors was validated using immunohistochemistry (IHC), immunofluorescence (IF), and H&E staining. Relative growth kinetics between PCC and NPCC organoids were measured and compared. Sizes of subcutaneously xenografted tumors harbored by mice representing different types of GC organoids were analyzed. We further examined drug sensitivities between docetaxel, 5-fuorouracil (5-FU), oxaliplatin, and irinotecan against our collected samples of patient-derived organoids. The impact of cancer-associated fibroblasts (CAFs) on organoid growth and chemoresistance was analyzed via co-culture experiments.ResultsOrganoids retained genetic and histopathological features of primary tumors. PCC-derived organoids displayed rapid growth characteristics in vitro and produced more rapidly growing tumors in vivo than NPCC. PCC organoids showed heightened sensitivity to docetaxel with lower IC50, but no significant differences were observed for 5-FU, oxaliplatin, or irinotecan. CAF co-culture enhanced organoid proliferation and conferred resistance to all tested chemotherapeutic agents.ConclusionPatient-derived GC organoids especially PCC subtypes reliably recapitulate the complexity of solid-tumors heterogeneity, predict drug responses, and elucidate stromal contributions to therapy resistance. This model could be used to develop tailoring treatments and improve personalization of therapy for clinical management of PCC.https://www.frontiersin.org/articles/10.3389/fmolb.2025.1631168/fullgastric cancer (GC)patient-derived organoidspoorly cohesive carcinoma (PCC)drug sensitivitytumor microenvironment |
| spellingShingle | Yi Yin Yi Yin Shuhong Zeng Shuhong Zeng Shuhong Zeng Hui Zhang Hui Zhang Shuangshuang Wang Fei Ke Qiang Rui Jinyong Zhou Yuwen Zhuang Weixing Shen Weixing Shen Jun Qian Jun Qian Shenlin Liu Shenlin Liu Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinoma Frontiers in Molecular Biosciences gastric cancer (GC) patient-derived organoids poorly cohesive carcinoma (PCC) drug sensitivity tumor microenvironment |
| title | Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinoma |
| title_full | Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinoma |
| title_fullStr | Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinoma |
| title_full_unstemmed | Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinoma |
| title_short | Patient-derived gastric cancer organoids model heterogeneity and stroma-mediated chemoresistance in poorly cohesive carcinoma |
| title_sort | patient derived gastric cancer organoids model heterogeneity and stroma mediated chemoresistance in poorly cohesive carcinoma |
| topic | gastric cancer (GC) patient-derived organoids poorly cohesive carcinoma (PCC) drug sensitivity tumor microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2025.1631168/full |
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