A multi-gene expression signature in tumors is associated with aggressive disease and poor patient outcomes, and it has the potential to become a biomarker for genetic cancer.
The mitochondria, the primary energy source of the human cell, play an important role in the metabolism of cancer cells. In a recently published study in PLOS ONEresearchers from around the world, including Dario C. Altieri, MD, president and chief executive officer, director of the Ellen and Ronald Caplan Cancer Center, and Robert and Penny Fox Distinguished Professor at The Wistar Institute, have identified a particular gene signature that is indicative of is for of mitochondrial reprogramming in tumors associated with poor patient outcome.
“To our knowledge, this is the first time that a gene signature of mitochondrial dysfunction has been linked to aggressive cancer subtypes, treatment resistance and, unfortunately, low patient survival rates. While our work has focused on the mitochondrial protein Mic60 in this response, we do not know that dysfunctional mitochondria are often generated during tumor growth, suggesting that this is a common trait in cancer,” says Altieri.
This study is inspired by previous work investigating the role of the Mic60 protein in tumor cell proliferation, motility and metastasis. Mic60, also known as mitophilin or inner membrane mitochondrial protein (IMMT), is a key protein required for mitochondrial structure and therefore affects mitochondrial functions and tumor metabolism.
Andrew Kossenkov, Ph.D., first author of the paper, assistant professor in Wistar’s Gene Expression and Regulation program, and scientific director of the Institute’s Bioinformatics Facility, shares: “Following original findings on the strong association of Mic60 in low levels in cancerous tissues, we were curious if we could identify a small panel of Mic60 downstream genes with specific functions and if the signature of the Mic60 low gene panel has clinical relevance – i.e. if it relates to clinical data such as survival , cancer subtypes, response to treatment, etc. – and we did.”
Armed with this knowledge, the team – along with collaborators from Canada, Italy and the United States – analyzed tumor cells from three independent patient cohorts with pancreatic ductal adenocarcinoma (PDAC). They showed that an 11-gene Mic60 low signature is associated with aggressive disease, local inflammation, treatment failure and shorter survival – ultimately demonstrating the protein’s clinical relevance. Therefore, the Mic60 low gene signature can be used as a simple tool or biomarker to estimate cancer risk for PDAC and potentially other types of cancer, including glioblastoma.
“Gene signatures can be used to gain insight into specific tumor qualities,” Kossenkov explains. “If it has been extensively developed, tested and validated, this is [Mic60-low gene signature] may be a potentially simple point-of-service molecular tool for pancreatic cancer prognosis or patient risk stratification and treatment response prediction.”
“While the broad applicability of this new Mic60 low gene signature certainly awaits further confirmation in larger patient populations, we hope that this simple, easy-to-implement molecular tool in the clinic will help stratify patients at higher risk of severe and progressive disease’, details Altieri.
With regard to future directions, Kossenkov suggests that studying broader datasets with extensive clinical information not limited to pancreatic cancer, but also other malignancies, may help demonstrate the applicability of the 11gene Mic60-low signature in cancer risk estimation.
Reference: “Mitochondrial Fitness and Cancer Risk” By Andrew V. Kossenkov, Andrew Milcarek, Faiyaz Notta, Gun-Ho Jang, Julie M. Wilson, Steven Gallinger, Daniel Cui Zhou, Li Ding, Jagadish C. Ghosh, Michela Perego, Annamaria Morotti , Marco Locatelli, Marie E. Robert, Valentina Vaira and Dario C. Altieri, October 12, 2022, PLOS ONE.
The study was funded by the National Institutes of Health and the Ontario government.