Revisiting seed and soil: A new approach to target hibernating dormant tumor cells

Over hundred and thirty years have passed since Stephen Paget proposed his ‘Seed and Soil’ hypothesis about metastatic spreading (1). Since then, we have gained a better insight into the complexities of this multistep dispersal, but we are yet to fully comprehend the interactions governing the metastatic ecosystems to enable us to clinically prevent disease recurrence and, ultimately, cancer-related deaths.

Despite the high inefficiency of the metastatic process (2), cancer patients often suffer late recurrences following five to thirty years of undetectable disease (3, 4). This clinical observation is due to the presence of disseminated tumour cells (DTCs) that escape early from the primary tumour and spread to distant organs. Once there, DTCs may initially lie in a dormant or hibernating state to later reawaken, resulting in incurable metastatic outgrowths (5, 6). Dormant DTCs persist in a non-proliferative but reversible arrest, and consequently are resistant to conventional therapies directed towards rapidly dividing cancer cells. Moreover, they adapt to the metastatic niche they reside in, evading the immune system and reactivating tumour-initiating abilities when the opportunity arises (7, Weidenfeld and Barkan) (see (7) for concept definitions to avoid terminology misconceptions).

Therefore, metastatic dormancy represents a major clinical problem, as well as a novel window of opportunity to hamper metastatic relapse by interfering with the dormant cancer cell life cycle [key steps to control dormancy in (7)].

In this Research Topic, we revisited Paget’s hypothesis focusing on the dormant phase of metastatic progression. This 10-article collection provides an overview on recent advances in the dormancy field, including original research on organ-specific mechanisms driving the reawakening of DTCs; and comprehensive and exhaustive reviews about the microenvironmental regulation of dormancy and reawakening, cutting-edge technologies to study interactions with the metastatic microenvironment and innovative therapeutic strategies to clinically monitor and target this undetectable stage of metastatic disease.