Assessing the Role of Intracellular PTHrP Signaling in Mechanisms of Tumor Dormancy
Abstract
Breast cancer cells frequently spread to the bone, where they will either grow into a secondary tumor and destroy the bone, resulting in pain and fractures, or they will remain as a single or small cluster of tumor cells that do not cause any damage (termed dormant tumor cells). Nearly 70% of patients with breast cancer that succumb to the disease have tumor cells in the bone. Dormant tumor cells may eventually be re-activated to grow into a secondary tumor, leading to breast cancer recurrence in patients. It is not understood why or how dormant tumor cells are woken up, but it is imperative that we find out, since this could provide new treatment strategies to eliminate the tumor cells and prevent recurrence in patients. Our proposed research plan is focused on determining why/how breast cancer cells lie dormant for years and then re-emerge and how to prevent lethal recurrence. When tumor cells settle in the bone marrow, they begin making a protein called parathyroid hormone-related protein (PTHrP), which causes the bone to break down and release other proteins that accelerate the growth of the cancer cells in the bone. Recently, my collaborators and I discovered that PTHrP may also help the dormant cells awaken and cause recurrence, but we do not know how PTHrP is able to do this. PTHrP can be cut up in the cells into lots of fragments called peptides. Our data demonstrate that one of those PTHrP peptides (which we can make by deleting different parts of the protein) keeps tumor cells dormant in the primary tumor site, but awakens dormant tumor cells in the bone, resulting in tumor recurrence in bone (bone metastases). We have found that in cells that express this particular PTHrP peptide, there is a family of genes that is more strongly expressed, called epithelial-to-mesenchymal (EMT) genes. These genes generally cause tumor cells to become more aggressive, but can also slow down their replication. Based on data from our lab and others, we hypothesize that the PTHrP peptide keeps cells dormant by stimulating an EMT gene called transforming growth factor beta (TGFbeta) to slow down proliferation but causes dormant tumor cells in bone to awaken by stimulating a gene called programmed death ligand 1 (PD-L1) that brings in immune cells, which ultimately causes the bone to break down and release proteins that signal to the tumor cells to start replicating. We will test this hypothesis by deleting and restoring those genes that are regulated by the PTHrP peptide and observing how this impacts tumor dormancy. PD-L1 is called an immune checkpoint protein, which can be clinically targeted using immune checkpoint inhibitors. These types of inhibitors are highly effective at extending patient survival in many tumor types and can even cure cancer in some patients where it has spread to other places in the body (metastatic disease). However, these inhibitors have not worked as well in breast cancer. Our study will determine whether PTHrP peptides control the expression of PD-L1 on tumor cells in the bone, and we will test whether cells that express this form of PTHrP are more sensitive (i.e., more of the cells die) in response to FDA-approved immunotherapy. While these studies are just the beginning steps in working out how PTHrP controls tumor dormancy, if our hypothesis is correct, it would suggest that immunotherapy might kill off dormant tumor cells in the bone marrow if they express this particular marker, which may prevent recurrence and extend survival for patients with breast cancer. If this is correct, future studies would determine whether the presence of these PTHrP peptides can predict which patients will benefit from immunotherapy, and whether we can turn on expression of this peptide to sensitize the cells. Ultimately, these studies will determine whether we can extend the survival benefits of immunotherapy to patients with dormant breast tumor cells in the bone, who are at high risk for lethal
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210090
Entities
People
- Rachelle Johnson
Organizations
- United States Army
- Vanderbilt University