Mitochondria Mic60 and cancer

Mitochondria are key components in the production of energy in human cells and play an important role
in cancer cell metabolism.
In a research paper published in PLOS ONE, Dario C.
Altieri, M.
D.
, along with national and international collaborators, distinguished a specific genetic signature that indicates the programming
of mitochondrial body weight in tumors associated with poor patient outcomes.

"To our knowledge, this is the first time that genetic signatures of mitochondrial dysfunction have been found to be associated
with aggressive cancer subtypes, treatment resistance, and unfortunately low patient survival.
Although our work has focused primarily on the mitochondrial protein Mic60 in this response, we know that dysfunctional mitochondria are often produced during tumor growth, suggesting that this is a universal feature of cancer," Altieri said
.

This paper stems from past research
on the role of the Mic60 protein in tumor cell proliferation, motility and metastasis.
Mic60, also known as mitofilin or inner membrane mitochondrial protein (IMMT), is a key protein that is critical for mitochondrial structure and therefore has downstream effects
on mitochondrial function and tumor metabolism.

Dr.
Andrew Kossenkov, first author of the paper, assistant professor in the Wistar Gene Expression and Regulation Program and scientific director of the Institute's Bioinformatics Facility, shared: "Following the original discovery of a strong association of Mic60 at low levels in cancer tissue, we were curious to see if we could identify a small group of specific functions of genes downstream of Mic60, and whether the features of the Mic60-low genome were clinically relevant – i.
e.
, If it correlates with clinical data such as survival, cancer subtype, treatment effect, etc.
– we did
.
”

Armed with this knowledge, the team, along with collaborators from across Canada, Italy, and the United States, analyzed tumor cells
from three separate cohorts of pancreatic ductal adenocarcinoma (PDAC) patients.
They showed that an 11-gene Mic60-low signature was associated with aggressive disease, local inflammation, treatment failure, and shortened survival—conclusively demonstrating the protein's clinical relevance
.
Thus, the Mic60-low gene marker can be used as a simple tool or biomarker to estimate cancer risk for PDAC and potentially other types of cancer, including glioblastoma
.

Kossenkov explains: "Genetic signatures can be used to gain insight into specific tumor quality
.
If widely developed, tested, and validated, this (Mic60-low gene signature) could become a potentially simple point-of-service molecular tool
for pancreatic cancer prognosis or patient risk stratification and treatment response prediction.
”

Altieri elaborated: "While the widespread application of this new Mic60-low gene signature certainly needs further confirmation in larger patient populations, we hope that this simple, easy-to-implement molecular tool will help clinically stratify
patients at higher risk of severe and progressive disease.
"

Regarding the way forward, Kossenkov suggested studying a broader dataset containing a wide range of clinical information, not just for pancreatic cancer, but also for other malignancies, which could help demonstrate the applicability of the
11-gene Mic60-low feature in estimating cancer risk.

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, Dario C.
Altieri.
Mitochondrial fitness and cancer risk.
PLOS ONE, 2022; 17 (10): e0273520