It is nowadays widely accepted that a tumor mass can release circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) into the blood stream of cancer patients. The analysis of these circulating tumor components is referred to as “liquid biopsy”. In the last years, the liquid biopsy field has become one of the most intensively researched areas of oncology and may become an integral part of cancer diagnostics. Beside the technical advances in analysis of liquid biopsies, it is widely unknown which mechanisms lead to the release of CTCs and ctDNA. Factors such as apoptosis or necrosis, inflammation as well as tumor heterogeneity may play an important role in spreading of metastatic disease. But to effectively supress tumor cell dissemination, and thereby deadly metastatic disease, we have to understand the causal factors. Therefore our research focus lies in “tracking the trace” of the liquid biopsy back to their tumor origin. We thereby investigate liquid biopsy components in blood and link the obtained information with the histological- and immunological composition of the originating tumor tissue. We thereby implement novel spatial in situ sequencing technologies, to directly sequence mutations in the tumor tissue without losing the histological composition. By using this approach we aim to establish a yet undefined “tissue-to-liquid biopsy” model of tumor cell dissemination. This may reveal valuable insights in the mechanisms of the first steps of metastasis formation and potentially how to supress it.