Mechanisms of dormant breast cancer cell communication with their environment - Project Summary/Abstract Recurrent metastases represent the main hurdle in curing breast cancer (BCa) patients. These are fueled by a fraction of disseminated cancer cells (DCCs) that enter a transient non-proliferative state known as dormancy, which enables them to resist chemotherapeutics and environmental challenges until conditions are favorable for them to re-activate and thrive as metastases. Thus, understanding dormant DCCs (dDCCs) and their interactions with the surrounding environment is essential for identifying strategies to eliminate these latent killers and prevent metastatic relapse of BCa patients. My preliminary studies indicate that the HIRA-mediated incorporation of non-canonical histone H3.3 is a key cell-intrinsic mechanism that regulates dDCCs' fate and that responds to the environment, including host factors such as obesity and aging. These studies also indicate that this HIRA/H3.3 axis of chromatin regulation controls specific defense mechanisms in dDCCs that protect them from immune responses. Based on these findings, I hypothesize that the HIRA/H3.3 axis serves as a central communication hub between dDCCs and their micro- and macro-environment, allowing for immune escape and survival during the dormant period and is responsive to obesity to induce reawakening from dormancy. During the K99 phase of this award, I will determine the regulatory network that controls HIRA re- expression and consequent dDCC reawakening in response to obesity. I will also initiate studies focused on defining dDCC-triggered immunoediting that allows for escape from immune response. During the R00 phase of this award, I will determine the paracrine signaling inducing immune evasion, as well as use unbiased approaches to define the surfaceome of dDCCs and focus on developing CAR-T cell-based therapy for dDCCs targeting. These studies will give rise to new discoveries about the biology of dDCCs and their interaction with the environment, including how these are shaped by obesity, a major risk factor for breast cancer relapse, and consequently pave the way for innovative therapies to eliminate dDCCs, potentially offering a definitive cure for BCa patients. In addition to the scientific goals of this proposal, I have also proposed a comprehensive training plan during the K99 phase of the award that will prepare me for the transition to independence. This includes guidance from three renowned mentors, Drs. Ana Gomes, Paulo Rodriguez, and Brian Czerniecki; acquisition of new skills in tumor immunology and breast oncology; training on state-of-the-art technology for CAR-T cell development and single-cell RNA sequencing analyses; as well as mastering the professional skills needed to guide my transition to independence and my success as an independent principal investigator.
