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Tumor heterogeneity and cancer stem cell properties in renal cancer

English title Tumor heterogeneity and cancer stem cell properties in renal cancer
Applicant Moch Holger
Number 166391
Funding scheme Project funding (Div. I-III)
Research institution Institut für Klinische Pathologie Departement für Pathologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Clinical Cancer Research
Start/End 01.06.2016 - 30.11.2020
Approved amount 450'500.00
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Keywords (5)

intratumoral heterogeneity; Stem cells; Renal Cell Carcinoma; Genomics; VHL

Lay Summary (German)

Lead
Den verschiedenen Tumorzelleigenschaften im Nierenkrebs auf der Spur
Lay summary
Nierenkrebs ist schwer zu behandeln, da diese Tumoren häufig in späten Stadien entdeckt werden und schlecht auf eine Bestrahlung oder Chemotherapie ansprechen. Ein Grund für diese Situation ist die Eigenschaft der Krebszellen, innerhalb des Tumors und der Tumorabsiedelungen (Metastasen) sehr unterschiedliche Eigenschaften aufzuweisen. Allen Nierenkrebszellen gemeinsam ist eine genetische Veränderung (Mutation) im sogenannten Von-Hippel-Lindau-Gen. Diese Genveränderung ist für die Entstehung des Nierenkrebses verantwortlich, ihr Nachweis sagt aber nichts über das Ansprechen auf die Chemotherapie aus. In den letzten Jahren wurden zahlreiche weitere DNA-Veränderungen identifiziert, die jedoch nur in bestimmten Tumorzellgruppen in einem Tumor oder dessen Metastasen vorkommen. Es wird sogar postuliert, dass einzelne Tumorzellpopulationen sogenannte „Stammzelleigenschaften“ besitzen, die die Metastasierung dieser Tumoren so unvorhersehbar machen. Insgesamt ist also das Nierenkarzinom aus genetischer Sicht sehr heterogen. In diesem Projekt wird daher versucht, „Stammzelleigenschaften“ im Nierenkrebs zu identifizieren und ausserdem seltene Tumorzellpopulationen nachzuweisen, die das Metastasierungsverhalten beeinflussen. Um den aggressivsten („bösartigsten“) Tumorzellklon nachzuweisen, werden Tumorzellen aus menschlichen Tumoren in Kultur gebracht oder in Mausmodelle übertragen. Durch solche Modelle können seltene und aggressive Tumorzellpopulationen besser identifiziert werden und deren Bedeutung für den Patienten nachgewiesen werden. Mit diesem Projekt wollen wir die Tumorzelleigenschaften kleiner Populationen besser erkennen und charakterisieren, um in der Zukunft eine individualisiertere und bessere Therapie für Nierenkrebspatienten anzubieten.
Direct link to Lay Summary Last update: 10.05.2016

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
135792 VHL-abhängige und unabhängige Mechanismen des Nierenzellkarzinoms. Ueberführung in klinische Anwendungen 01.01.2012 Project funding (Div. I-III)
118356 Uncovering the VHL-regulated proteome in human renal cell cancer - implications for renal cancer biology and therapy 01.10.2007 Project funding (Div. I-III)

Abstract

Clear cell renal cell carcinoma (ccRCC), the most common type of renal cancer, is characterized byasymptomatic manifestation in early stage and a poor response to radiotherapy and chemotherapy inmetastatic stage, making this tumor very difficult to diagnose early and to treat. For this reason, newdiagnostic and predictive biomarkers for renal cancer are needed.For several years, inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene has been considered the main cause of ccRCC. Therefore, drugs that specifically target the pathways activated by VHL loss of function have been tested for treatment. With these novel therapeutic approaches partial success was achieved in progression free and overall survival, but only a minority of ccRCC patients responded in combination with considerable side effects to these treatment modalities.Recently, additional tumor suppressor genes have been found mutated in ccRCC, some of them withsignificant prognostic implications. However, which of those gene alterations leads to increased metastatic potential has to be elucidated. Additionally, whether a cancer stem cell population exists in ccRCC and / or a cancer cell branch harboring these mutations which have stem cell properties is not known. Supporting the hypothesis of having cancer cell subpopulations with or without stemness character is that ccRCC seems to be a very heterogeneous tumor. This is reflected by the fact that multiple samples derived from the same ccRCC revealed in 25% a higher similarity to unrelated ccRCC samples. To elucidate these open questions, we will establish primary ccRCC cell lines and study the mutationalprofile, the expression pattern on RNA and protein level in relation to in vitro characteristics such asproliferation and invasion. Furthermore, we will assess the fraction of cancer stem cells by side population and sphere assays and identify dominant cancer cell subpopulations giving rise to tumors and related metastases in mice. To investigate the influence of the microenvironment for the selection and outgrowth of a specific clone we will as well compare the tumors and metastases in mice derived from primary cell lines and its corresponding minced primary tumor tissue. Furthermore, we will assess the genotypic and phenotypic stability of the primary cell lines and xenografts during multiple passages. Of all these passages we plan to collect cancer stem cells capable of forming spheres and with enrichment potential. These spheres will be analysed as well in depth for their genotype by next-generation sequencing and for specific (cc)RCC cancer stem cell markers using qPCR arrays, immunohistochemistry, and Mass Spectrometry / Cytometry.The final goal of this project is to identify cancer driver mutations in ccRCC responsible for its metastaticpotential and to elucidate whether these mutations are occurring in a stem cell population or branch more resistant to chemo- and radiotheraphy. Secondly, this project aims to define phenotypic markers of this subpopulation. The combination of the knowledge of the genomic profile and expression pattern of such a subpopulation will potentially promote the discovery of more accurate and reliable diagnostic tools of ccRCC.
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