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A renal cell carcinoma tumorgraft platform to advance precision medicine.

ABSTRACT: Renal cell carcinoma (RCC) encompasses a heterogenous group of tumors, but representative preclinical models are lacking. We previously showed that patient-derived tumorgraft (TG) models recapitulate the biology and treatment responsiveness. Through systematic orthotopic implantation of tumor samples from 926 ethnically diverse individuals into non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice, we generate a resource comprising 172 independently derived, stably engrafted TG lines from 148 individuals. TG lines are characterized histologically and genomically (whole-exome [n = 97] and RNA [n = 102] sequencing). The platform features a variety of histological and oncogenotypes, including TCGA clades further corroborated through orthogonal metabolomic analyses. We illustrate how it enables a deeper understanding of RCC biology; enables the development of tissue- and imaging-based molecular probes; and supports advances in drug development.

SUBMITTER: Elias R

PROVIDER: S-EPMC8762721 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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A renal cell carcinoma tumorgraft platform to advance precision medicine.

Elias Roy R Tcheuyap Vanina T VT Kaushik Akash K AK Singla Nirmish N Gao Ming M Reig Torras Oscar O Christie Alana A Mulgaonkar Aditi A Woolford Layton L Stevens Christina C Kettimuthu Kavitha Priya KP Pavia-Jimenez Andrea A Boroughs Lindsey K LK Joyce Allison A Dakanali Marianna M Notgrass Hollis H Margulis Vitaly V Cadeddu Jeffrey A JA Pedrosa Ivan I Williams Noelle S NS Sun Xiankai X DeBerardinis Ralph J RJ Öz Orhan K OK Zhong Hua H Seshagiri Somasekar S Modrusan Zora Z Cantarel Brandi L BL Kapur Payal P Brugarolas James J

Cell reports 20211101 8

Renal cell carcinoma (RCC) encompasses a heterogenous group of tumors, but representative preclinical models are lacking. We previously showed that patient-derived tumorgraft (TG) models recapitulate the biology and treatment responsiveness. Through systematic orthotopic implantation of tumor samples from 926 ethnically diverse individuals into non-obese diabetic (NOD)/severe combined immunodeficiency (SCID) mice, we generate a resource comprising 172 independently derived, stably engrafted TG l ...[more]

PMID: 34818533

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Project description:BackgroundDespite the significant advances in the management of advanced prostate cancer (PCa), metastatic PCa is currently considered incurable. For further investigations in precision treatment, the development of preclinical models representing the complex prostate tumor heterogeneity are mandatory. Accordingly, we aimed to establish a resource of patient-derived xenograft (PDX) models that exemplify each phase of this multistage disease for accurate and rapid evaluation of candidate therapies.MethodsFresh tumor samples along with normal corresponding tissues were obtained directly from patients at surgery. To ensure that the established models reproduce the main features of patient's tumor, both PDX tumors at multiple passages and patient's primary tumors, were processed for histological characteristics. STR profile analyses were also performed to confirm patient identity. Finally, the responses of the PDX models to androgen deprivation, PARP inhibitors and chemotherapy were also evaluated.ResultsIn this study, we described the development and characterization of 5 new PDX models of PCa. Within this collection, hormone-naïve, androgen-sensitive and castration-resistant (CRPC) primary tumors as well as prostate carcinoma with neuroendocrine differentiation (CRPC-NE) were represented. Interestingly, the comprehensive genomic characterization of the models identified recurrent cancer driver alterations in androgen signaling, DNA repair and PI3K, among others. Results were supported by expression patterns highlighting new potential targets among gene drivers and the metabolic pathway. In addition, in vivo results showed heterogeneity of response to androgen deprivation and chemotherapy, like the responses of patients to these treatments. Importantly, the neuroendocrine model has been shown to be responsive to PARP inhibitor.ConclusionWe have developed a biobank of 5 PDX models from hormone-naïve, androgen-sensitive to CRPC primary tumors and CRPC-NE. Increased copy-number alterations and accumulation of mutations within cancer driver genes as well as the metabolism shift are consistent with the increased resistance mechanisms to treatment. The pharmacological characterization suggested that the CRPC-NE could benefit from the PARP inhibitor treatment. Given the difficulties in developing such models, this relevant panel of PDX models of PCa will provide the scientific community with an additional resource for the further development of PDAC research.

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A renal cell carcinoma tumorgraft platform to advance precision medicine.

Publications

A renal cell carcinoma tumorgraft platform to advance precision medicine.

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