A renal cell carcinoma tumorgraft platform to advance precision medicine

doi:10.1016/j.celrep.2021.110055

Cell Reports

Volume 37, Issue 8, 23 November 2021, 110055

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https://doi.org/10.1016/j.celrep.2021.110055 Get rights and content

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Highlights

•
Generation of a large PDX library from a diverse population
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The PDX library is characterized by next-generation sequencing (exome and RNA-seq)
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Interactive tool for selecting TG lines representative of RCC molecular subtypes
•
Precision diagnostics and therapeutic applications illustrated

Summary

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.

Graphical abstract

Keywords

animal models

BAP1

belzutifan

biomarkers

HIF

immunoPET

iPET

kidney cancer

metabolomics

molecular imaging

NGS

patient-derived xenograft (PDX)

PET

PT2385

radiotracer

renal cell carcinoma (RCC)

VHL

TAK-243

Data and code availability

Tumorgraft sample raw sequencing data files (WES and RNaseq) for patients providing consent (n = 121 samples) (see Table S7) have been deposited to the European Genome-phenome Archive (EGA). Data can be accessed at the following EGA Study ID: EGAS00001005516. All code used to analyze the data is listed in the key resources table and is publicly available. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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¹²: These authors contributed equally

¹³: Present address: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 401 N. Broadway, Baltimore, MD 21231, USA

¹⁴: Present address: Departments of Urology and Oncology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA

¹⁵: Present address: Department of Oncology, Hospital Clinic de Barcelona and Translational Genomic and Targeted Therapeutics in Solid Tumors, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/ Villarroel 170, Barcelona, Spain

¹⁶: Present address: Bristol-Myers Squibb, 4931 George Rd, Tampa, FL 33634, USA

¹⁷: Present address: SciGenom Research Foundation, Bangalore, Karnataka, India

¹⁸: Lead contact