Serine-Induced Glycosylation in Progression and Metastasis of ccRCC
Abstract
Background: Kidney cancer is the seventh most common type of cancer in the United States with over 81,000 new cases and 14,000 deaths estimated in the year 2023. Metastatic clear cell renal cell carcinoma (ccRCC) is the most common type of renal carcinoma (85% of all kidney cancer), with a median survival rate of about 13 months, and is refractory to chemotherapy. Cancer cells are armored with specialized metabolic pathways to support enhanced proliferation, metastasis, and immune evasion. Aberrant metabolic reprogramming in the uptake and metabolism of amino acids is one of the hallmarks of cancer cells. Serine is the second most nonessential amino acid utilized next to glutamine by cancer cells and is produced by the serine biosynthesis pathway. The first enzyme in the serine biosynthesis pathway, PHGDH, is reduced in ccRCC. Hence, unlike many other cancers, ccRCC depends on the exogenous serine availability for their proliferation and survival. Interestingly, this dependency makes serine a conditionally essential amino acid in ccRCC, but also presents opportunities to target serine-related metabolism for a therapeutic target against ccRCC. So far, the role of serine in the development of primary tumors has been extensively studied; however, it is not clear if availability of serine impacts metastasis. Metastasis is, so far, the major driver of cancer-related deaths. In this proposal, we aim to further expand our understanding of metabolic vulnerability due to the loss of PHGDH in ccRCC. This study aims to test if serine restriction can be augmented with existing therapy to enhance the efficacy of primary treatments. State the KCRP Area(s) of Emphasis the project addresses: Basic Biology Research - Tumor metabolism, tumor progression and metastasis Describe the ultimate applicability of the research: Understanding gained from the successful completion of this proposal will enable us to strategize the targeting of specific pathways and factors mediated through serine usage and serine-induced glycosylation for therapeutic approaches. What types of patients will it help, and how will it help them? In general, this study will help to target cancers that are dependent on exogenous serine for proliferation and survival. Restriction of serine usage will cause reduction in the metastatic potential of ccRCCs. What are the potential clinical applications, benefits, and risks? If the research is too basic for clinical applicability, describe the interim outcomes expected and their applicability to the field. Dietary restriction augmented with other therapeutic options is the ultimate clinical application envisioned. The understanding of the serine, glycosylation, metastatic potential is the expected interim outcome. What are the likely contributions of this study to advancing the field of kidney cancer research? Glycosylation is a biologically necessary modification of proteins with implications in both normal development and disease. It is one of the abundant and complex modifications that are frequently demonstrated during neoplastic transformation. However, the impact of serine-induced glycosylation has not yet been explored. Cancer-specific glyco-diversification supports neoplastic progression and unique alterations in tumor biology and metabolism. However, there is no comprehensive information on the glycosylation status in ccRCC. Our study potentially leads to identification of serine-dependent glycan signatures as prognostic markers. Furthermore, serine-induced aberrant glycosylation may generate ccRCC-specific neoantigens, which can be targeted for therapeutic purposes. How is the project relevant to military Service Members, Veterans, and their families? The etiology of the kidney cancer is not well understood, however, our Service Members and Veterans are constantly exposed to some of the known risk factors including smoking tobacco, environmental and occupational exposures to to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310341
Entities
People
- Suman Karki
Organizations
- United States Army
- University of Alabama at Birmingham