Clonal heterogeneity influences drug responsiveness in renal cancer assessed by <i>ex vivo</i> drug testing of multiple patient‐derived cancer cells

Saeed, Khalid; Ojamies, Poojitha; Pellinen, Teijo; Eldfors, Samuli; Turkki, Riku; Lundin, Johan; Järvinen, Petrus; Nísen, Harry; Taari, Kimmo; Hällström, Taija M. af; Rannikko, Antti; Mirtti, Tuomas; Kallioniemi, Olli; Östling, Päivi

doi:10.1002/ijc.31815

Cited by 32 publications

(25 citation statements)

References 37 publications

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“…We enlarged evaluation of cancer organoids as drug testing model exploring the activity of on-going trial drugs based on multi-kinases inhibition i.e SU11274, Foretinib, Cabozantinib and Levantinib in combination with Everolimus. Normal and tumor organoids isolated from two selected patients were characterized as mutational patterns by Sanger sequencing looking at the most frequent lesions recently associated at therapy in renal cancer 48 (Supplementary Fig. 16–18).…”

Section: Resultsmentioning

confidence: 99%

“…Short Tandem Repeat Analysis for sample Identification in organoid and parental derivative tissues were performed with AmpFℓSTR™ Identifiler™ PCR Amplification Kit (Catalog Number 4322288 Thermofisher Scientific). Mutation scanning of the specific variants selected among frequently published (Saeed K. et al 48 and TCGA genome ATLAS 49 ) was performed by Sanger sequencing using an ABI Prism 3500 Genetic Analyzers (Applied Biosystems) and the ABI BigDye Terminator Sequencing Kit V.3.1 (Applied Biosystems). Primer pairs designed to amplify a specific coding regions of PBMR1, TSC2, VHL, KDM5C, SETD2 and PIK3C2A genes are listed in online Supplementary Information.…”

Section: Methodsmentioning

confidence: 99%

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Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases

et al. 2019

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The pressure towards innovation and creation of new model systems in regenerative medicine and cancer research has fostered the development of novel potential therapeutic applications. Kidney injuries provoke a high request of organ transplants making it the most demanding system in the field of regenerative medicine. Furthermore, renal cancer frequently threaten patients’ life and aggressive forms still remain difficult to treat. Ethical issues related to the use of embryonic stem cells, has fueled research on adult, patient-specific pluripotent stem cells as a model for discovery and therapeutic development, but to date, normal and cancerous renal experimental models are lacking. Several research groups are focusing on the development of organoid cultures. Since organoids mimic the original tissue architecture in vitro, they represent an excellent model for tissue engineering studies and cancer therapy testing. We established normal and tumor renal cell carcinoma organoids previously maintained in a heterogeneous multi-clone stem cell-like enriching medium. Starting from adult normal kidney specimens, we were able to isolate and propagate organoid 3D-structures composed of both differentiated and undifferentiated cells while expressing nephron specific markers. Furthermore, we were capable to establish organoids derived from cancer tissues although with a success rate inferior to that of their normal counterpart. Cancer cultures displayed epithelial and mesenchymal phenotype while retaining tumor specific markers. Of note, tumor organoids recapitulated neoplastic masses when orthotopically injected into immunocompromised mice. Our data suggest an innovative approach of long-term establishment of normal- and cancer-derived renal organoids obtained from cultures of fleshly dissociated adult tissues. Our results pave the way to organ replacement pioneering strategies as well as to new models for studying drug-induced nephrotoxicity and renal diseases. Along similar lines, deriving organoids from renal cancer patients opens unprecedented opportunities for generation of preclinical models aimed at improving therapeutic treatments.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases

et al. 2019

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“…The PDC cultures that we derived largely retained the characterizing molecular features defining ccRCC evolutionary subtypes during serial passaging and consequently represent attractive tools to study the role of subclones in invasion, metastasis, or therapy resistance. Interestingly, a complementary proof-of-concept study recently indicated the impact of spatial tumor heterogeneity on drug response patterns by establishing PDC cultures from different tumor regions and highlighting their distinct drug response profiles [27]. While truncal driver mutations inherited by all cancer cells could be exploited to find common drug efficacies, PDC models provide the prerequisite to investigate drug response profiles specific to subsets of patients.…”

Section: Discussionmentioning

confidence: 99%

Tracing Clonal Dynamics Reveals that Two- and Three-dimensional Patient-derived Cell Models Capture Tumor Heterogeneity of Clear Cell Renal Cell Carcinoma

Bolck

Corrò

Kahraman

et al. 2021

European Urology Focus

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Background: Extensive DNA sequencing has led to an unprecedented view of the diversity of individual genomes and their evolution among patients with clear cell renal cell carcinoma (ccRCC). Objective: To understand subclonal architecture and dynamics of patient-derived two-dimensional (2D) and three-dimensional (3D) ccRCC models in vitro, in order to determine whether they mirror ccRCC inter-and intratumor heterogeneity. Design, setting, and participants: We have established a comprehensive platform of living renal cancer cell models from ccRCC surgical specimens. Outcome measurements and statistical analysis: We confirmed the concordance of 2D and 3D patient-derived cell (PDC) models with the original tumor tissue in terms of histology, biomarker expression, cancer driver mutations, and copy number alterations. We addressed inter-and intrapatient heterogeneity by analyzing clonal dynamics during serial passaging. Results and limitations: In-depth genetic characterization verified the presence of heterogeneous cell populations, and revealed a high degree of similarity between subclonal compositions of monolayer and organoid cell cultures and the corresponding parental ccRCCs. Clonal dynamics were evident during serial passaging of cells in vitro, suggesting that PDC cultures can offer insights into evolutionary potential and treatment susceptibility of ccRCC subclones in vivo. Proof-of-concept drug profiling using selected ccRCC-targeted therapy agents highlighted patient-specific vulnerabilities in PDC models that could not be anticipated by interrogating commercially available cell lines. Conclusions: We demonstrate that PDC models mirror inter-and intratumor heterogeneity of ccRCC in vitro. Based on our findings, we envision that the use of these models will advance our understanding of the trajectories that cause genetic diversity and their consequences for treatment on an individual level. Patient summary: In this study, we developed two-and three-dimensional patient-derived models from clear cell renal cell carcinoma (ccRCC) as "mini-tumors in a dish." We show that these cell models retain important features of the human ccRCCs such as the profound tumor heterogeneity, thus highlighting their importance for cancer research and precision medicine.

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“…e intravascular portion of the renal tumor is not typically biopsied and would be invasive, which is why we focused on the intratumor microbiota profile. Primary renal tumor tissue can be biopsied, but does suffer from genetic heterogeneity and is one of the controversies regarding renal biopsy accuracy for precision medicine and stratification in clinical trials [21][22][23].…”

Section: Discussionmentioning

confidence: 99%

Microbiome within Primary Tumor Tissue from Renal Cell Carcinoma May Be Associated with PD-L1 Expression of the Venous Tumor Thrombus

Liss¹,

Chen²,

Rodríguez³

et al. 2020

Advances in Urology

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Objective. To perform a proof of concept microbiome evaluation and PD-L1 expression profiling in clear-cell renal cell carcinoma (cc-RCC) with associated tumor thrombus (TT). Methods. After IRB approval, six patients underwent radical nephrectomy (RN) with venous tumor thrombectomy (VTT). We collected fresh tissue specimens from normal adjacent, tumor, and thrombus tissues. We utilized RNA sequencing to obtain PD-L1 expression profiles and perform microbiome analysis. Statistical assessment was performed using Student’s t-test, chi-square, and spearman rank correlations using SPSS v25. Results. We noted the tumor thrombus to be mostly devoid of diverse microbiota. A large proportion of Staphylococcus epidermidus was detected and unknown if this is a surgical or postsurgical contaminant; however, it was noted more in the thrombus than other tissues. Microbiome diversity profiles were most abundant in the primary tumor compared to the thrombus or normal adjacent tissue. Differential expression of PD-L1 was examined in the tumor thrombus to the normal background tissue and noted three of the six subjects had a threshold above 2-fold. These three similar subjects had foreign microbiota that are typical residents of the oral microbiome. Conclusion. Renal tumors have more diverse microbiomes than normal adjacent tissue. Identification of resident oral microbiome profiles in clear-cell renal cancer with tumor thrombus provides a potential biomarker for thrombus response to PD-L1 inhibition.

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Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient‐derived cancer cells

Cited by 32 publications

References 37 publications

Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases

Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases

Tracing Clonal Dynamics Reveals that Two- and Three-dimensional Patient-derived Cell Models Capture Tumor Heterogeneity of Clear Cell Renal Cell Carcinoma

Microbiome within Primary Tumor Tissue from Renal Cell Carcinoma May Be Associated with PD-L1 Expression of the Venous Tumor Thrombus

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