Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits
Abstract An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address, this we developed an extensive series of 27 patie...
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Springer Nature
2020-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201911889 |
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| author | Lidia Moserle Roser Pons Mar Martínez‐Lozano Gabriela A Jiménez‐Valerio August Vidal Cristina Suárez Enrique Trilla José Jiménez Inés de Torres Joan Carles Jordi Senserrich Susana Aguilar Luis Palomero Alberto Amadori Oriol Casanovas |
| author_facet | Lidia Moserle Roser Pons Mar Martínez‐Lozano Gabriela A Jiménez‐Valerio August Vidal Cristina Suárez Enrique Trilla José Jiménez Inés de Torres Joan Carles Jordi Senserrich Susana Aguilar Luis Palomero Alberto Amadori Oriol Casanovas |
| author_sort | Lidia Moserle |
| collection | DOAJ |
| description | Abstract An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address, this we developed an extensive series of 27 patient biopsy‐derived orthotopic xenograft models (Ren‐PDOX) that represent inter‐patient heterogeneity. In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species‐discriminative RNA sequencing identified a tumor cell‐specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion‐annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro‐invasive subtype of Ren‐PDOXs. Validation in an independent series of 15 antiangiogenic‐treated patients confirmed that pre‐treatment ALDH1A3 can significantly discriminate patients with pro‐aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment. |
| format | Article |
| id | doaj-art-37c72f66a1ce49acaeef8a135ab7206f |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-37c72f66a1ce49acaeef8a135ab7206f2025-08-20T03:05:55ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-11-01121211710.15252/emmm.201911889Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traitsLidia Moserle0Roser Pons1Mar Martínez‐Lozano2Gabriela A Jiménez‐Valerio3August Vidal4Cristina Suárez5Enrique Trilla6José Jiménez7Inés de Torres8Joan Carles9Jordi Senserrich10Susana Aguilar11Luis Palomero12Alberto Amadori13Oriol Casanovas14Tumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELLTumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELLTumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELLTumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELLDepartment of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), CIBERONCMedical Oncology Department, Vall d’Hebron HospitalSurgery Department, Vall d’Hebron HospitalMedical Oncology Department, Vall d’Hebron HospitalPathology Department, Vall d’Hebron HospitalMedical Oncology Department, Vall d’Hebron HospitalTumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELLTumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELLProCURE Program, Catalan Institute of Oncology. OncoBell Program, IDIBELLDepartment of Surgery, Oncology and Gastroenterology, University of PadovaTumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELLAbstract An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address, this we developed an extensive series of 27 patient biopsy‐derived orthotopic xenograft models (Ren‐PDOX) that represent inter‐patient heterogeneity. In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species‐discriminative RNA sequencing identified a tumor cell‐specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion‐annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro‐invasive subtype of Ren‐PDOXs. Validation in an independent series of 15 antiangiogenic‐treated patients confirmed that pre‐treatment ALDH1A3 can significantly discriminate patients with pro‐aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment.https://doi.org/10.15252/emmm.201911889antiangiogenicsbiomarkercancer resistancemetastasis inductionorthotopic models of kidney cancer |
| spellingShingle | Lidia Moserle Roser Pons Mar Martínez‐Lozano Gabriela A Jiménez‐Valerio August Vidal Cristina Suárez Enrique Trilla José Jiménez Inés de Torres Joan Carles Jordi Senserrich Susana Aguilar Luis Palomero Alberto Amadori Oriol Casanovas Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits EMBO Molecular Medicine antiangiogenics biomarker cancer resistance metastasis induction orthotopic models of kidney cancer |
| title | Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits |
| title_full | Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits |
| title_fullStr | Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits |
| title_full_unstemmed | Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits |
| title_short | Kidney cancer PDOXs reveal patient‐specific pro‐malignant effects of antiangiogenics and its molecular traits |
| title_sort | kidney cancer pdoxs reveal patient specific pro malignant effects of antiangiogenics and its molecular traits |
| topic | antiangiogenics biomarker cancer resistance metastasis induction orthotopic models of kidney cancer |
| url | https://doi.org/10.15252/emmm.201911889 |
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