An extramedullary bone model to study metastatic dormancy reveals a piecemeal model for metastatic reactivation.

Abstract Metastatic relapse can occur months to years after the cancer is first diagnosed, and it relies on the reactivation of disseminated tumour cells (DTCs) that have lied dormant in secondary organs. The acquisition and maintenance of a dormancy phenotype are tightly regulated by the interaction of DTCs with their microenvironment. In the bone, the dormant program activated in metastatic competent cells and how their reactivation is induced are largely unknown. We here present a strategy to engineer a mouse-to-mouse extramedullary (EM) bone, which faithfully recapitulates endogenous bone and that can induce the acquisition of dormancy in highly metastatic breast cancer cells. By characterising the dormant state of metastatic cells, we found that they persist in two distinct transcriptional states: a more abundant quiescent and a less abundant proliferative state. The local environment influences the ratio between the two states. We found that an inflammatory mediator expressed by neutrophils progenitors, HMGB2, can contribute to nudging DTCs into an increased proliferation. Indeed, waves of emergency granulopoiesis expanding the neutrophils pool caused by inflammatory events such as intestinal colitis, expanded the proliferative pool of DTCs without resulting in a direct outgrowth. However, these events, progressively augmented the amount of DTCs in the bone, increasing the chance of overt metastasis. Therefore, this study proposes a piecemeal model of metastatic reactivation, where subsequent inflammatory events challenging the bone environment progressively increase the likelihood of outgrowth over time as opposed to a sudden switch from dormancy to metastasis.