Breast cancer-related fatalities often stem from the tumor’s metastatic spread to distant organs, a phenomenon that can manifest years after treatment of the primary tumor. The period of remission can become a time of apprehension for patients, fostering a constant threat of relapse. These seeds of metastasis may spread from the early stage of primary tumor growth by disseminated cancer cells (DCCs), establishing a dormant presence in distant organs for extended periods before inciting metastatic relapse. While it is recognized that the “awakening” of DCCs after initial seeding depends, in part, on microenvironmental signals, the intricate details of this process remain largely elusive.
This project’s objective is to comprehend the influence of age-related clonal hematopoiesis (CH) on reactivating these dormant DCCs. CH is characterized by somatic mutations in hematopoietic stem cells that confer a growth advantage and lead to clonal expansion in the hematopoietic compartment and can serve as a precursor to hematologic malignancies. Notably, the incidence of CH increases with age. It is also now understood that CH can also affect the risk of progression for solid tumors. However, how CH contributes to the awakening of DCCs is unknown. Julio Aguirre-Ghiso and Ross Levine hypothesize that the pre-existing or subsequent acquisition of age-associated CH causes the expansion of pro-inflammatory, mutant myeloid effector cells that shape the microenvironment around dormant DCCs, leading to a loss of homeostasis and reactivation of dormant DCCs.
The project will explore the impact of CH on various stages of the metastatic process, including intravasation, conversion from dormant DCCs to metastasis, and metastatic growth maintenance in target organs. Additionally, the investigators plan to study the role of CH in modulating the immune landscape, tissue resident macrophages, and clonal representation of DCCs and CH populations within the metastatic ecosystem. The project will employ Cite-seq analysis, organoid co-cultures, and the administration of interleukins to uncover the mechanisms by which CH-regulated myeloid secreted factors induce breast cancer DCC awakening in the lung. This exploration into how CH contributes to metastatic progression by reactivating dormant DCCs represents uncharted territory, potentially uncovering how host cell mutations act as drivers of metastasis and offering novel opportunities for prognosis and intervention to prevent and treat metastatic relapse linked to age-associated CH.