Epigenetic and metabolic bottlenecks of tumorigenesis - Recurrent metastasis is the leading cause of breast cancer mortality. Dormancy is a critical, but poorly understood, step in the tumorigenic process where breast cancer cells can remain in a non-proliferative state at secondary sites for long periods of time after successful treatment of the primary tumor. Reactivation of dormant breast cancer cells (dDCCs) enables recurrent metastatic disease often resistant to standard of care therapies, and as such dDCCs represent a major clinical obstacle in breast cancer patient care. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive cell fate transitions. However, little is known about the nature of this remodeling in the context of dormancy. Our published work demonstrated that as breast cancers acquire the ability to disseminate, canonical histone H3 incorporation into chromatin is suppressed and replaced by a rare histone H3 variant, H3.3, incorporated by its cognate histone chaperone, HIRA. This switch in histone composition is sufficient and necessary to enable dissemination and consequently promote breast cancer metastasis. Our subsequent studies revealed that HIRA is not only important for acquiring metastatic ability within the primary tumor but also for controlling the transition between dormant and proliferative states, thereby serving as a major regulator for the fate of DCCs. Thus, here we propose that H3.3 deposition driven by the HIRA complex regulates breast DCCs’ fate through the metastatic cascade, determining whether the cells enter and remain dormant or proliferate and form overt metastases. This hypothesis will be tested through three specific aims: Aim 1 will focus on establishing H3.3 deposition into chromatin as the effector of HIRA in regulating the proliferation to dormancy switch in breast DCCs and the specific mechanism by which HIRA-mediated H3.3 deposition exerts its effects while aim 2 will focus on precisely defining the inflection points in the metastatic cascade regulated by HIRA-mediated H3.3 deposition and their metabolic/redox requirements. Aim 3 on the other hand will focus on defining the role of the HIRA-H3.3 chromatin remodeling axis in mediating the interaction between the lung environment and the fate of dormant cancer cells. Successful completion of these studies will unveil for the first time a major regulator of the epigenetic remodeling that drives the establishment of and exit from dormancy. Consequently, the proposed studies will put forward HIRA as an important therapeutic target to prevent reawakening and consequently the active recurrence of metastatic breast cancer. Moreover, our studies will enable the unbiased discovery of redox and metabolic pathways that support vitality of the different cell states during the metastatic cascade enabling future studies aimed at evaluating said pathways as much needed liabilities with therapeutic relevance to eradicate dormant cells and effectively prevent recurrent metastatic breast cancer.
