Advanced Science (Sep 2024)
Primary and Orthotopic Murine Models of Nasopharyngeal Carcinoma Reveal Molecular Mechanisms Underlying its Malignant Progression
- Xudong Wan,
- Yuantao Liu,
- Yiman Peng,
- Jian Wang,
- Shu‐mei Yan,
- Lu Zhang,
- Wanchun Wu,
- Lei Zhao,
- Xuelan Chen,
- Kexin Ren,
- Haicheng Long,
- Yiling Luo,
- Qin Yan,
- Lele Zhang,
- Dengzhi Lei,
- Pengpeng Liu,
- Shujun Li,
- Lihui Liu,
- Linjie Guo,
- Jiajia Du,
- Mengsha Zhang,
- Siqi Dai,
- Yi Yang,
- Hongyu Liu,
- Nianyong Chen,
- Jinxin Bei,
- Lin Feng,
- Yu Liu,
- Mu‐sheng Zeng,
- Chong Chen,
- Qian Zhong
Affiliations
- Xudong Wan
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Yuantao Liu
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Yiman Peng
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Jian Wang
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Shu‐mei Yan
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Lu Zhang
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Wanchun Wu
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Lei Zhao
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Xuelan Chen
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Kexin Ren
- Department of Otolaryngology West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Haicheng Long
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Yiling Luo
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Qin Yan
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Lele Zhang
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Dengzhi Lei
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Pengpeng Liu
- Department of Hematology West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Shujun Li
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Lihui Liu
- Department of Otolaryngology West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Linjie Guo
- Department of Gastroenterology West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Jiajia Du
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Mengsha Zhang
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Siqi Dai
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Yi Yang
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Hongyu Liu
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Nianyong Chen
- Department of Otolaryngology West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Jinxin Bei
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Lin Feng
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Yu Liu
- Department of Biotherapy State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Mu‐sheng Zeng
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- Chong Chen
- Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 China
- Qian Zhong
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Department of Experimental Research Sun Yat‐sen University Cancer Center Sun Yat‐sen University Guangzhou Guangdong 510060 China
- DOI
- https://doi.org/10.1002/advs.202403161
- Journal volume & issue
-
Vol. 11,
no. 36
pp. n/a – n/a
Abstract
Abstract Nasopharyngeal carcinoma (NPC), a squamous cell carcinoma originating in the nasopharynx, is a leading malignancy in south China and other south and east Asia areas. It is frequently associated with Epstein‐Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV‐ (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in TP53. To investigate the functional roles of NPC‐associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene‐edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that Trp53 and Cdkn2a deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV‐coding oncoprotein, significantly promoted the distal metastasis. Further, loss of TGFBR2, which is frequently disrupted both in EBV‐ and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.
Keywords