Mitochondrial lateral transfer during metastasis

About This Grant

Project Summary Macrophages play paradoxical roles in cancer: They can be tumoricidal, but in many cancers, macrophages promote metastasis. There has been growing evidence that macrophages can modulate cell behavior via unconventional cell contact-mediated communication in development and homeostasis. We have recently extended these paradigms by discovering that macrophages laterally transfer mitochondria to breast cancer cells, promoting cancer cell proliferation. Mitochondria are dynamic organelles that perform a variety of essential cellular functions. Mitochondria have been shown to transfer to tumor cells in vivo, restoring their respiration and ability to form tumors. While these elegant “proof of principle” studies demonstrated that mitochondrial lateral transfer can occur in the tumor microenvironment, it was unclear how a relatively small population of exogenous mitochondria changes the behavior of the recipient cancer cell, particularly if the recipient cancer cell already has a functional endogenous mitochondrial network. In now recently published work, we found that transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species. Accumulated reactive oxygen species at transferred mitochondria then promotes breast cancer cell proliferation in an ERK-dependent manner. These results suggest that transferred mitochondria do not promote cancer cell proliferation via restoration of bioenergetics. Rather, transferred mitochondria act as a signaling source, promoting cancer cell behaviors. These unexpected findings led us to ask whether this form of communication is specific to macrophages and cancer cells, or whether mitochondrial transfer between other cells in the tumor environment use this process to regulate proliferation. This question forms the basis of the extension period of the R37 award. Our preliminary results suggest that mitochondrial transfer between cancer cells may use different strategies, and thus, in updated aim 1, we propose to determine the mechanism by which mitochondrial transfer between cancer cells promotes cancer cell proliferation. We will also determine whether mitochondrial transfer from highly metastatic cancer cells promote metastatic behaviors of recipient weakly metastatic cells in vitro and in vivo. Furthermore, in updated aim 2, we have excitingly built a new tool to detect mitochondrial transfer with higher sensitivity, allowing us to delve into new mechanisms underlying mitochondrial transfer. Taken together, these experiments will reveal how mitochondrial transfer instructs breast cancer cells to become more robust and metastatic. Our goals are to define how immune cells function in the tumor microenvironment, and to provide a basis for developing future immunotherapies that limit metastasis.