Roles of CTC: PMN-MDSC Clusters in Melanoma Brain Metastasis
Abstract
There are multiple aspects of novelty in this proposal that introduce new concepts and ideas, and make inroads to better understand the biology of melanoma. Melanoma is a very aggressive cancer that is increasing in frequency and responsible for more than 80% of all skin cancer-related deaths. Moreover, melanoma has a tendency to spread rapidly throughout the body – a process called metastasis – and possesses highest abilities to colonize the brain (up to 80% of patients at autopsy). Melanoma brain metastasis (MBM) carries a dismal diagnosis, with a median survival of only 2-4 months. If patients develop brain leptomeningeal disease, survival is even lower. Therefore, MBM is not only a devastating disease but is also incredibly frightening for patients, given the extremely low survival rate and the very few treatment options. For example, while recently developed targeted therapies and immunotherapies have slowed down melanoma progression, patients develop drug resistance within months following treatment, significantly limiting therapy efficacy. Circulating Tumor Cells (CTCs) are a necessary pre-condition for metastasis to occur. While millions of CTCs are shed from tumors every day, only few become capable of surviving and migrating to distant organs, giving rise to metastasis. Mechanistically, how a CTC quiescent state is induced, maintained, and deactivated by environmental cues remain a fundamental question to address, particularly given the increasing relevance of the immune system regulating tumor dormancy and metastasis. Importantly, properties of CTCs which allow them to metastasize to the brain are not understood. This proposal is designed to discover the fundamental characteristics of CTCs in their interactions with a type of cells of the immune system: Polymorphonuclear-Myeloid Derived Suppressor Cells (PMN-MDSCs). We have discovered that patient-isolated CTCs cluster and interact with circulatory MDSCs isolated from the same patient. The underlying cellular and molecular mechanisms of these clusters of CTCs with MDSCs are therefore critical to understand because they can be far more dangerous to the melanoma patient than single CTCs. Moreover, the presence of CTC clusters at baseline has been proven to be associated with shorter progression-free survival/overall survival in patients. Studies proposed have therefore high biological and clinical relevance because outcomes of malignant melanoma greatly vary among patients, ranging from curable (complete remission) to highly metastatic and lethal. CTCs can undergo dramatic phenotypic changes resulting in highly proliferative and/or metastasis-competent CTCs. The focus of my laboratory is to study CTCs with the objectives of developing tests clinically useful for early detection - predicting MBM – and/or therapy intervention - preventing MBM. The rarity of CTC:PMN-MDSC clusters necessitates the use of highly sophisticated and accurate technologies to capture and interrogate them. We reported the presence of subsets of CTCs which express markers of cell proliferation, indicating that CTCs have left quiescence and entered a state of proliferation and potential metastatic competence. Strikingly, these CTCs express genes known to directly interact with PMN-MDSCs. The pioneering studies delineating cellular crosstalks between patient-isolated CTCs and PMN-MDSCs are also innovative because the interactions with PMN-MDSC cells induce sweeping changes in CTC capabilities to form tumors. They yielded stunning results by discovering novel CTC pathways regulating the exit of CTCs from quiescence. Such profound roles by both cell types in the transition from dormant to metastasis-active states had not been foreseen and merit further investigation. We will test a combination of medication pre-clinically, e.g., using inhibitors already developed, blood-brain barrier (BBB) permeable, and non-toxic in animals. We expect that these treatments using CTC
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210877
Entities
People
- Dario Marchetti
Organizations
- Health Sciences Center, University of New Mexico
- United States Army