CEVIR

a. Background and rationale.
Cancer is an evolutionary process where the units of selection, the cancer cells, are constantly reacting and changing in response to environmental and iatrogenic selection pressures. It is therefore not surprising that the previous focus on molecular studies of primary tumours in order to select therapy targets falls short with the need of striking a moving target.
b. Hypothesis.
Systemically disseminated cancer cells are often substantially different from the primary tumour. However, it is largely unknown which cells are able to survive systemic therapies and which mechanisms are involved in cell survival and progression to lethal metastasis in patients. Therefore, we need tools to monitor systemic cancer over the course of time. Secondly, to identify relapse-initiating cells, we need to unravel their origin. Are relapse-initiating cells derived from the most aberrant and most distant descendant of the cancerous progeny or are the seeds of relapsing metastases much closer to the root of the cancer cell kindred? Knowing the answer to this fundamental question will enable to select the right markers to monitor systemic cancer and eventually help to administer the most appropriate therapy for the actual stage of the disease.
c. Aims.
CEVIR (ceviri, turk: translation) aims to translate an evolutionary understanding of cancer into monitoring assays that guide treatment decisions. Cancer cells and molecules such as nucleic acids can be found within the blood stream over the course of disease and provide valuable information about this evolutionary process. However, major hurdles to exploit blood-borne biomarkers are detection limits for circulating tumour cells (CTCs) or nucleic acids and the differentiation of disease-driving mechanisms from epiphenomena. CEVIR will address both hurdles.
d. Methods.
We will improve CTC detection. Then, to monitor cancer evolution, it is essential to know what to monitor. For this, we will genetically determine the relapse initiating cells (RICs) by use of lineage tree analysis, generated from primary tumours, disseminated cancer cells from lymph nodes and CTCs from follow-up samples. Genetic and epigenetic profiling will unravel the molecular features of RICs. This information will then be used to establish monitoring assays, employing DNA mutations and methylation patterns isolated from plasma with and without extravesicular enrichment.
e. Expected results and potential impact.
We will answer whether RICs are derived from late arising rapidly dividing clones of the primary tumour or from rarely-dividing stem-like cells similar to some types of leukaemia and use this information for the development of blood-borne monitoring assays. By tracking RICs back to the earliest seeds of systemic disease, we will also develop monitoring assays for early systemic cancer and explore whether these characteristics are functionally relevant and possibly useful therapy targets.