Investigating macrophage-to-tumor mitochondrial transfer

Project Summary Tumor metastasis is the leading cause of cancer related mortalities, yet preventing this malignant phenotype continues to elude scientific investigators. In efforts to understand what factors promote malignant cancer behavior, the tumor microenvironment has become an intense focus of study and tumor-infiltrating macrophages

have been shown to contribute to poor prognosis. We aimed to better understand how macrophage-tumor cell interactions promote aggressive tumor phenotypes. In this effort, we demonstrated that macrophages transfer bulk cytoplasmic material directly to tumor cells and that recipient cells exhibit enhanced migration in vitro and

dissemination in vivo. Recently, we set out to determine what material is transferred during these interactions. Using primary human macrophages and human breast cancer cells, we observed that macrophages transfer mitochondria to breast cancer cells. Importantly, cancer cells that received macrophage mitochondria also

exhibited enhanced cell proliferation, a critical step of the metastatic cascade. We then aimed to determine whether macrophage polarization influenced mitochondrial transfer and observed that pro-tumorigenic M2-like macrophages exhibit enhanced rates of mitochondrial transfer. Since Notch signaling has been shown to

influence macrophage polarization, we set out to determine whether Notch signaling also influences the transfer of mitochondria and found that the inhibition of Notch signaling resulted in increased rates of macrophage mitochondrial transfer and promoted M2-like macrophage phenotypes. These findings have set forth the

proposed investigation of macrophage-to-tumor mitochondrial transfer. By utilizing in vitro and in vivo models we will investigate mitochondrial transfer from primary mouse pro-tumorigenic Tumor Associated Macrophages and determine how their mitochondrial dynamics influence mitochondrial transfer. Furthermore, we will determine

how Notch signaling influences these processes and subsequent mitochondrial transfer. Given that Notch signaling inhibitors are currently under clinical pursuit for the treatment of breast cancer, these data present an enticing premise: if inhibition of Notch signaling promotes mitochondrial transfer and subsequent tumor

proliferation, what basic biology may be overlooked in the context of this treatment? In this proposal we will shift the focus from post-transfer tumor cell phenotypes to pre-transfer macrophage biology and how these phenotypes may be influencing mitochondrial transfer. Importantly, the proposed focus on pre-transfer biology

of the mitochondrial ‘donor’ cell and what dynamic properties promote mitochondrial transfer have not been investigated. Our work will illuminate a currently unappreciated mechanism of macrophage-associated tumorigenicity. By providing insights to how foundational macrophage biology and Notch signaling influence

macrophage-to-tumor mitochondrial transfer, this work will help guide clinical efforts of Notch inhibition and prime future investigations of macrophage-tumor interactions to prevent mitochondrial transfer and hinder the metastatic cascade.