An extramedullary bone model of metastatic dormancy reveals an increased rate of metastatic reactivation upon distant insults

Authors list

Stefania Di Blasio Tatiana Rizou Laurie Gay Nick Rabas Probir Chakravarty Thomas Snoeks Adam Karoutas Felipe Rodrigues Vicky Bridgeman Xuanxuan Fan Elodie Montaudon Elisabetta Marangoni Dominique Bonnet Ander Abarrategi Ilaria Malanchi

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Abstract

Metastatic relapse in the bone can occur months to years after the cancer is first diagnosed, and it relies on the reactivation of disseminated tumour cells (DTCs) that have lain dormant in secondary organs. This process is tightly regulated by the host tissue microenvironment. However, our understanding of dormancy remains limited due to the challenges of experimentally recapitulating host-induced DTC reawakening. Here, we present a tuneable, skeletal progenitor-based engineered extramedullary (EM) bone in mice that faithfully recapitulates endogenous bones and effectively induces dormancy in metastatic breast cancer cells. During EM bone development in vivo, we observed that metastatic cancer cells acquire a dormant phenotype, persisting in a quiescent state with sporadic transient proliferative events. This model provides a unique platform to investigate how this acquired dormant state is regulated and how it can be perturbed. We found that inflammatory events leading to emergency granulopoiesis increase the proliferative fraction of dormant cells. Importantly, we validated this boosting effect in endogenous bones. Specifically, we identified High-Mobility Group Box 2 (HMGB2) as a factor that enhances the likelihood of overt metastasis. Furthermore, we exploited the ability to time-tune the EM bone environment by inducing local release of specific factors, confirming HMGB2’s role in increasing the risk of metastatic outgrowth. Overall, our findings establish the EM bone as a powerful discovery model for studying bone dormancy.