Role of Vascular Mimicry in the Outgrowth of Dormant Melanoma Micrometastases
Abstract
Since I started my laboratory in 2014 my research has focused on understanding the mechanisms involved in melanoma brain metastasis, for which I have established a research pipeline using an integrated proteogenomics approach and novel brain metastasis models that I developed. My current lab-based efforts are related to furthering our understanding of how the micrometastatic tumor microenvironment controls the outgrowth of dormant lesions. I have been heavily involved in the development of a translational melanoma brain metastasis research program at Yale, with the goal of developing new drugs and delivering personalized therapy for melanoma patients with brain metastases. These studies are part of a broader endeavor ongoing at Yale aimed at changing treatment paradigms for brain metastasis patients. One of the biggest mysteries of melanoma, but other cancers as well, is how disseminated cancer cells can be dormant in distant organs for years, only to emerge later on as clinically difficult to cure lesions. The factors regulating the transition from dormant to progressively growing metastases continue to be understudied and not understood. This proposal focuses on establishing the importance of a scarcely studied process called vascular mimicry, in which cancer cells contribute to the formation and lining of functional blood vessels in tumors, and their acquisition of increased blood supply during expansion. Our preliminary work using novel preclinical models we have developed led to the hypothesis that vascular mimicry could be linked to the switch from dormancy to proliferative state in organs poorly vascularized such as the brain; therefore, the focus of these studies on brain metastatic melanoma. If proven true, this could have broad implications ranging from predilection to develop early metastasis and accelerated disease to ineffectiveness of drugs currently used in clinic to treat melanoma. Our application is highly responsive to the Melanoma Research Program Challenge Statement through its scope and addresses two specific Focus Areas: (1) it is designed to uncover new molecular pathways that influence melanoma dormancy and recurrence, and (2) it seeks to improve our understanding of how the tumor microenvironment, specifically neovascularization influences the transition from dormant state to progressive melanoma. If successful, our work will establish vascular mimicry as a potential weakness of brain metastatic melanomas, in that they may be reliant on a particular type of vasculature in the early stage during metastatic awakening, and might provide new opportunities to develop strategies to prevent expansion or stabilize dormant metastases. Our studies may provide a strong rationale for exploiting this process as a therapeutic target to prevent the proliferative outbreak of dormant micrometastases or perhaps to develop novel approaches to eradicate dormant tumor cells, thus preventing disease recurrence. Once melanoma metastasizes, it is typically treated with systemic therapies. In recent years major progress has been made in treating metastatic melanoma. However, studies that led to these advances have excluded patients with brain metastases and little is therefore known about systemic therapy for melanoma brain lesions. Moreover, there is a paucity of clinically relevant animal models of melanoma brain metastases. Therefore, my group has been developing resources to address these deficiencies in recent years, as described in the preliminary data sections. These resources will enable me to reach the goal of developing new drugs to either prevent or treat brain metastases and delivering personalized therapy for melanoma patients. From a translational perspective, I hope to bring discoveries to the clinic to improve our understanding and knowledge of metastatic disease and to improve patient care. If successful, these studies will decrease the morbidity and mortality from melanoma brain
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310670
Entities
People
- Lucia Jilaveanu
Organizations
- United States Army
- Yale University