Scientists have discovered a link between mitochondria and cancer

Illustration of dividing tumor cells

As of 2022, it is estimated that more than 600,000 people die from cancer each year in the United States.

This polygenic expression signature in tumors is associated with aggressive disease and poor patient outcomes, and has the potential to become an epigenetic cancer biomarker.

Mitochondria, the primary source of energy in the human cell, play an important role in the metabolism of cancer cells. In a study recently published in Plus oneAltieri, MD, President and CEO, and Director of the Eileen and Ronald Kaplan Cancer Center, and Robert and Penny Fox Distinguished Professor at the Wistar Institute, have identified a specific genetic signature indicative of mitochondrial reprogramming in tumors associated with outcome. bad for the patient.

Dario Altieri

Wistar Institute President and CEO Dr. Dario Altieri. Credit: Wistar Institute

To our knowledge, this is the first time that a genetic signature of mitochondrial dysfunction has been associated with aggressive subtypes of cancer, resistance to treatment and, unfortunately, low patient survival rates. Although our work has focused on the mitochondrial protein Mic60 in this response, we know that dysfunctional mitochondria are commonly generated during tumor growth, suggesting that this is a general feature in cancer,” says Altieri.

This study was inspired by previous work examining the role of the Mic60 protein in cancer cell proliferation, motility, and metastasis. Mic60, also known as mitofilyn or inner mitochondrial membrane protein (IMMT), is a major protein required for mitochondrial structure and thus has an impact on mitochondrial functions and tumor metabolism.

Andrew Kosenkoff, PhD, first author of the paper, associate professor in the Wistar Program for Gene Expression and Regulation, and scientific director of the institute’s Bioinformatics Facility, shares, “After original findings about the strong association of Mic60 with low levels in cancer tissues, we were curious if we could determine small panel of downstream Mic60 genes with specific functions and if the low Mic60 gene panel signature is of clinical relevance—that is, if it is associated with 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 across the United States—analysed tumor cells from three independent cohorts of patients with pancreatic ductal adenocarcinoma (PDAC). They show that a reduced signature of 11 Mic60 genes is associated with aggressive disease, local inflammation, treatment failure, and shortened survival—ultimately demonstrating the clinical significance of the protein. Therefore, the Mic60-low gene signature can be used as a simple tool or biomarker to estimate the cancer risk of PDAC and other types of cancer, including glioblastoma.

“Genetic signatures can be used to gain insight into specific tumor traits,” Kosenkoff explains. “If it is developed, tested and validated extensively, then this [Mic60-low gene signature] It could be a potential simple point-of-service molecular tool for pancreatic cancer prediction or patient risk stratification and treatment response prediction.”

“While the broad application of this new low Mic60 gene signature certainly awaits further confirmation in larger numbers of patients, we hope that this simple, easy-to-implement molecular tool will be useful in the clinic to stratify patients at higher risk for severe and progressive disease,” Altieri details. .

In terms of future directions, Kosenkoff suggests that examining broader datasets with comprehensive clinical information that is not limited to pancreatic cancer, but also other malignancies could help demonstrate the applicability of the reduced 11gene Mic60 signature in estimating cancer risk.

Reference: “Mitochondrial Fitness and Cancer Risk” by Andrew F. Kosenkoff, Andrew Melkirk, Fayaz Nota, Jun Hu Jang, Julie M Wilson, Stephen Gallinger, Daniel Cui Zhou, Li Ding, Jagadish C. Ghosh, Michela Perego, Annamaria Morotti, Marco Locatelli, Mary E. Robert, Valentina Vaira and Dario C. Altieri, 12 October 2022 Plus one.
DOI: 10.1371/journal.pone.0273520

The study was funded by the National Institutes of Health and the Government of Ontario.

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