The Mitochondrial Unfolded Protein Response Impacts Melanoma from Initiation to Patient Prognosis
Abstract
Every year within our health systems, we treat thousands of patients diagnosed with melanoma, yet we do not have a complete scientific understanding of how melanoma initiates nor how to clinically stratify patients for the likelihood of developing aggressive disease. Just over a decade ago when I started my laboratory, a mole on my leg started to look suspicious, and in that moment I contended with the same fears that the above patients bravely navigate. Unlike the majority of these patients, I recognized that my training as a mitochondrial biologist with interests in cancer afforded me the opportunity to develop an innovative research program to explore how melanoma initiates, and possibly, to identify new therapeutics. Over the past decade, my laboratory reported how the most commonly mutated pathway in melanoma (e.g., RAS-G12V & BRAF-V600E) impacts on mitochondrial biology – from the first steps towards disease – to how melanoma cells respond to targeted therapies (e.g., Vemurafenib). In parallel, using hundreds of melanoma patient samples, we applied our fundamental mitochondrial observations to generate unexpected clinical indicators of BRAF-V600E melanoma. To gain the resources necessary for these accomplishments, I formally requested an academic appointment in the Department of Dermatology at Mount Sinai Hospital. With this appointment, I gained access to dermatologist collaborations, dermato-pathology expertise, melanoma model systems, and patient samples, which empowered my group to quickly establish our melanoma research program. One unexpected outcome was my program became a magnet laboratory for medical students and residents who were interested in dermatology (with melanoma focus), and I have trained more than 10 physician scientists who are now dermatology faculty, chief residents, or just starting their residencies. Taken together, I have established scientific acumen, successful collaborations, and a lineage of clinical expertise – all without federal grants – that would be amplified by obtaining the Mid-Career Accelerator Award (MCAA). I am ready to interact with the melanoma community through our program, and this award would establish a solid financial foundation enabling me to focus on: science, deeper mentorship, the championing of students, and participation in the melanoma community as a leader. Rationale: The rationale behind this research program began by simply comparing mitochondria (the cellular powerhouse) in normal and senescent melanocytes (clusters of these cells form a mole) from patients. We observed that senescent melanocytes have undescribed amazingly large and inter-connected mitochondria that send signals to the cell’s DNA that something is wrong. We explored these signals and identified that mutant RAS/BRAF cause activation of a mitochondrial stress/repair pathway that governs growth, metabolism, and the secretion of factors involved in immune surveillance. We believe this mitochondrial pathway is an epicenter of disease initiation, prognosis, and treatment. Objectives: The objectives of this MCAA application are focused on understanding how mitochondrial stress signaling and repair instruct the development of melanoma and impact on the local immune environment surrounding melanomas. We will utilize state-of-the-art approaches coupled with patient samples and data to examine our science and generate molecular signatures of high-risk disease. Our Study Addresses the Fiscal Year 2021 (FY21) Melanoma Research Program (MRP) Challenge Statement by: investigating how mitochondrial stress signaling directly controls multiple steps in the early stages of the melanomagenesis process, including the first cellular responses to mutant RAS/BRAF, cancer metabolism, epigenetics, and how oncogenes influence the immune landscape around early disease. We also demonstrate a new proof-of-concept that blocking mitochondrial stress signaling directly prevents melanomagenesis and
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210872
Entities
People
- Jerry Chipuk
Organizations
- Icahn School of Medicine at Mount Sinai
- United States Army