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 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.

Synopsis Renal cell carcinoma (RCC) biopsy‐derived orthotopic xenograft models (PDOX) reveal patient‐specific induction of invasion and metastasis after antiangiogenics. Molecular characterization identifies ALDH1A3 as a pre‐treatment discriminator of pro‐malignant tumors that predicts response to therapy.

Patient's original histomorphologic and molecular characteristics were maintained in an extensive series of 27 patient biopsy‐derived orthotopic xenograft models (Ren‐PDOX).
Antiangiogenic treatment produced patient‐specific responses of increased invasiveness and metastatic dissemination in approximately half of the models studied.
By a novel technique of species‐discriminative RNA‐sequencing and subsequent filtering using patient data, the key molecular traits of pro‐invasive type of tumors was unraveled.
ALDH1A3 was clinically validated as a possible predictive factor of pro‐aggressiveness in 15 antiangiogenic‐treated RCC patients.

Lidia Moserle¹, Roser Pons¹, Mar Martínez‐Lozano¹, Gabriela A Jiménez‐Valerio¹, August Vidal², Cristina Suárez³, Enrique Trilla⁴, José Jiménez³, Inés Torres⁵, Joan Carles³, Jordi Senserrich¹, Susana Aguilar¹, Luis Palomero⁶, Alberto Amadori^7,⁸ and Oriol Casanovas¹

Tumor Angiogenesis Group, ProCURE Program, Catalan Institute of Oncology, OncoBell Program, IDIBELL, Barcelona, Spain
Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), CIBERONC, Barcelona, Spain
Medical Oncology Department, Vall d’Hebron Hospital, Barcelona, Spain
Surgery Department, Vall d’Hebron Hospital, Barcelona, Spain
Pathology Department, Vall d’Hebron Hospital, Barcelona, Spain
ProCURE Program, Catalan Institute of Oncology. OncoBell Program, IDIBELL, Barcelona, Spain
Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
Veneto Institute of Oncology IOV – IRCCS, Padua, Italy

Source: Lidia Moserle, Roser Pons, Mar Martínez‐Lozano et al. "Kidney Cancer PDOXs Reveal Patient‐specific Pro‐malignant Effects of Antiangiogenics and Its Molecular Traits." EMBO Mol Med. 2020. e11889.

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