Mitochondrial Horizontal Transfer in Triple-Negative Breast Cancer
Abstract
Cancer cells constantly interact with surrounding cells in the tumor. The communication between cancer cells and surrounding cells is often the reason behind the failure of cancer therapeutics. We seek to understand this communication in an effort to overcome these barriers. Macrophages are a component of the immune system. Their best known function is to “seek and destroy” foreign particles. However, in the tumor environment, macrophages have a very different role – macrophages can facilitate steps of metastasis by communicating with cancer cells and helping cancer cells leave the tumor, enter the blood stream, and even grow at the metastatic site. We discovered that macrophages can communicate with cancer cells by “spilling their contents” to cancer cells. Cancer cells that received macrophage contents were those that went on to metastasize; thus, we reasoned that perhaps some of the molecules in these macrophage contents could be used as a marker of metastatic cells in the clinic. Furthermore, our goal is to identify these molecules to potentially inhibit them to reduce metastasis-related deaths. In an effort to discover the identity of these molecules, we recently found that macrophages transfer an organelle called mitochondria directly to triple-negative breast cancer cells. Mitochondria are considered the powerhouse of the cell, fueling the cell with energy to perform distinct tasks. Because metastasis is an energy-consuming process, we predicted that cancer cells thieve mitochondria from macrophages to meet the energy demands for metastasis. However, we found that the mitochondria that are transferred to cancer cells are different in their functions than the rest of the mitochondrial network in the cancer cells. The transferred mitochondria send out high amounts of a signal that we hypothesize might trigger signaling pathways that regulate cancer cell proliferation. Our proposal aims to first understand how macrophages package mitochondria and transfer them to cancer cells, and second, how this transferred mitochondria contribute to cancer cell metastasis. We will use a combination of cell culture systems and cells derived from triple-negative breast cancer patients and visualize mitochondrial transfer in real time using high-resolution microscopy. We will also take purified preparations of macrophage mitochondria and directly inject them into cancer cells to determine whether mitochondria alone are sufficient to drive metastasis. Therapeutics targeting mitochondrial function are already being developed in the clinic. However, these drugs may not effectively target metastatic cancer cells, particularly if mitochondrial function is rapidly altered by mitochondrial transfer. If mitochondrial transfer is detected in patients, therapies focused on limiting macrophage infiltration and mitochondrial transfer should be implemented. Thus, with this work, we hope to reduce metastases that occur after initial diagnosis and treatment in an effort to prolong patients’ lives.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010591
Entities
People
- Minna Roh-johnson
Organizations
- United States Army
- University of Utah