Early Determinants of Melanoma Metastasis
Abstract
Our proposal directly addresses two Fiscal Year 2020 (FY20) Melanoma Research Program (MRP) Focus Areas: (1) Understanding the tumor microenvironment and (2) Bioengineering (e.g., computational, imaging) approaches to address diagnostics. Our proposed research responds to the FY20 MRP Challenge Statement by redefining the concept of preventing early stage, localized melanoma from spreading from the primary tumor to other parts of the body, by identifying tumor- and patient-specific characteristics associated with metastasis. Given that cutaneous melanoma presents on the skin’s surface, primary tumors are easily detectable by routine surveillance. Surgical excision of these lesions is typically curative, but some melanomas will reappear/recur at the primary site or develop in other organs/metastasize. While a greater depth of invasion and ulceration of the primary tumor are two features associated with a greater chance of recurrence/metastasis, it is unclear why certain tumors are more likely to recur or metastasize when controlling for these factors. Recent evidence suggests that protein expression differences within the tumor and in the cells surrounding the tumor (normal skin cells, immune cells, blood vessels, fat, etc.), also known as the microenvironment, may be responsible for cell states associated with aggressive tumor biology. We plan to characterize the evolution of DNA and RNA-level differences in the primary tumor and the micro-environmental compartments. We will investigate how the timing and location of protein expression changes both within a single host’s tumor-microenvironment and between unique hosts’ tumor microenvironments contribute to the likelihood of metastatic progression. To accomplish these goals, we will study newly developed mouse models that accurately reflect human disease and tumors resected from patients with known clinical outcomes. Our proposal incorporates cutting-edge artificial intelligence and protein-antibody staining technologies, which will map, in both space and time, newly discovered tumor and host-specific features that may make a patient more or less susceptible to recurrence/metastasis. While advancements in genomics and immunology have benefited the treatment of metastatic melanoma with the continuous improvement of targeted and immune checkpoint inhibitor therapies, they do not address the more efficient means to reduce morbidity and mortality by preventing metastasis altogether. Further, subsets of patients remain inherently resistant to readily available treatments, the reason for which remains unclear. Our approach to exploring the expression profiles of the primary tumor and surrounding microenvironment has the potential to bridge this gap. We expect to reveal new, early-stage markers that indicate a high metastatic potential. We predict that interactions between malignant and non-malignant cells present therapeutic vulnerabilities for intervention at early stages of disease. Moreover, the information gained could be leveraged to define new predictive models of metastasis in melanoma and other cancers, such as colorectal, breast, and thyroid. Our studies will reveal novel features inside the tumor or its microenvironment that might help clinicians stratify high- vs. low-risk patients for recurrence, which may enhance selection for adjuvant treatment in disease-free patients, reducing unnecessary exposures to toxic medications. Further, this research will elucidate potentially targetable tumor characteristics, which may catalyze hypothesis-driven investigations in developmental therapeutics for local and metastatic disease, providing alternative options for treatmentresistant patients. We anticipate these findings will have clinical utility in just a couple of years post-award, given the importance of rigorous independent validation studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110510
Entities
People
- Iman Osman
Organizations
- Grossman School of Medicine
- United States Army