10 March 2022
Shapeshifting cancer cells during liver metastasis formation
The groups of Oncode Investigators Hugo Snippert (UMC Utrecht), Jacco van Rheenen (Netherlands Cancer Institute) and Michiel Vermeulen (Radboud University), together with Onno Kranenburg (UMC Utrecht), Martijn Gloerich (UCM Utrecht) and Prisca Liberali (FMI, Basel) have characterized how a colorectal tumor cell evolves as soon as it metastasizes to the liver and delineated which events are critical to succeed. Their findings have been published in Cancer Research today.
Cancer stem cells are essential for growth of both primary colon cancers (CRC) and liver metastases. As a consequence, cancer stem cells have been considered for years to be the ‘source of evil’ for cancer patients. Hugo Snippert: “Indeed, it was quite a surprise a few years ago when the teams of Jacco van Rheenen and me showed that liver metastases from colon tumors in fact do not originate from cancer stem cells."
In their new paper, the investigators use patient biopsies, patient-derived tumor organoids, mouse models of colon cancer, and human tumor xenografts to show with high precision that stem cells only arise at a multicellular stage during metastasis formation (so-called micrometastasis). Functionally, they further document that the emergence of de novo stem cells coincides with continuation of growth. Otherwise, when stem cells fail to emerge in micrometastases, growth stagnates.
The successful outgrowth of micrometastases into large lesions is a rate-limiting step in the metastatic cascade. Albeit clinically relevant, their small size and sporadic nature make micrometastases difficult to detect and study. As a result, there is poor understanding of the first stages of metastasis formation in human CRC patients. This new study aimed to address this knowledge gap.
Hugo continues: “While studying the developmental trajectory of CRC cells during in vivo metastasis formation or during clonal organoid formation, we noticed a high degree of similarity in terms of cell fate dynamics, transcriptional changes over time and their functional consequences. Foremost, regardless of which cell type we used to initiate metastases or organoid formation from, we saw an almost immediate activation of a regenerative response in all cells. At first, this response is essential for cell survival. Subsequently, this so-called YAP response decreases over time, gradually permitting the cells to mature into a diverse palette of cellular phenotypes, including cancer stem cells. This symmetry breaking process during which a clump of tumor cells self-organizes into a cellular hierarchy where cancer stem cells fuel continued growth, seems highly conserved between patients, mice, organoids, normal and cancer cells."
Illustrative of the elusive nature of micrometastases is the phenomenon of metastatic latency in CRC patients. Here, micrometastases can remain dormant and undetected in the liver for years after surgical removal of the primary cancer, eventually regaining proliferative behaviour and resulting in clinically overt lesions.
The researchers now suggest that, based on their data, dormant micrometastases may very well be microscopic lesions that have not been able to break symmetry. The inability to generate functional cell types, including stem cells, might thus represent a tumor intrinsic failure underlying dormancy. Future research will aim to resolve why certain lesion fail to do so, uncover their intimate interactions with the tumor microenvironment and, crucially, discover what triggers their activation after years of dormancy. Permanent deactivation of dormant micrometastases, or their controlled sensitization them to classical chemotherapy could be attractive therapeutic strategies to prevent clinically overt liver metastases.