Objective: Discovery ofcurativetherapiesforrenalcellcarcinoma(RCC)ishamperedbylackofauthenticpreclinicalmodels.

Tumorgrafts, generatedbydirectimplantationofpatient-derivedtissuesintomice,havedemonstratedsuperiorabilitytopredicttherapeutic

response. Weevaluated “tissue slicegrafts” (TSGs) asanimprovedtumorgraftmodelofRCC.

Materials andmethods: Cores offreshRCCwereprecision-cutat300 mm andimplantedundertherenalcapsuleofRAG2−/−γC−/−

mice. Engraftmentrate,histology,biomarkerexpression,genetic fidelity, andmetastaticpotentialwereevaluated.Magneticresonance

imaging (MRI)wastestedasanoninvasivemethodtomeasuretumorvolume,andresponsetoatargetedtherapywasdetermined.

Results: All 13casesofRCCengraftedanddisplayedcharacteristichistologyandbiomarkers.TSGvolumequantified noninvasivelyby

MRI highlycorrelatedwithgraftweights,providingauniquetoolformonitoringorthotopicgrowth.Moreover,in2cases,cancercellsfrom

TSGs metastasizedtoclinicallyrelevantsites,includingbone.MicroarrayanalysisandDNAsequencingdemonstratedahighdegreeof

correlation ofglobalgeneexpressionandvonHippel-Lindau(VHL)statusbetweenTSGsandparentaltumors.TreatmentofTSGswith

sunitinib significantly decreasedgraftweightandmeanvesseldensitycomparedwithcontrols.

Conclusion: The TSGmodelofRCCfaithfullyrecapitulatestumorpathology,geneexpression,geneticmutation,anddrugresponse.The

high engraftmentrateandmetastaticpotentialofthisauthenticmodel,inconjunctionwiththeabilitytogeneratelarge first-generation animal cohorts andtoquantitatetumorvolumeattheorthotopicsitebyMRI,proffersignificant advantagescomparedwithotherpreclinical platforms.