Pancreatic carcinoma as a mitochondrial disease
A gene signature for mitochondrial dysfunction is associated with aggressive tumour subtypes, treatment resistance and low survival rates.
Unlike most cancers, the 5- and 10-year survival rates for pancreatic cancer have not improved significantly since the early 1970s.1 It is predicted to replace colon cancer as the second leading cause of cancer-related deaths by 2030.2 To mark 'Pancreatic Cancer Awareness Month' in November, we would like to draw attention to an exciting recent paper that highlights the role of the cells' power plants, the mitochondria, in the development of pancreatic cancer.3,4
Mitochondrial performance and cancer risk are linked
A research team from the Wistar Institute (Philadelphia, USA) has found a new answer to what makes this cancer so particularly aggressive.
They recently discovered a group of human tumours with significantly downregulated expression of the mitochondrial structural protein Mic60, also known as mitofilin. Mic60 is predicted to be a core component in the assembly and maintenance of the inner membrane, which regulates cristae morphology, protein transport, mitochondrial DNA transcription, and the connection between the inner and outer mitochondrial membranes.5
Consequently, the Mic60-deficient tumours were characterised by massive loss of mitochondrial function, but at the same time showed an increased propensity for metastasis, upregulation of interferon (IFN) signalling pathways, and an increased propensity for the so-called senescence-associated secretory phenotype (SASP).
Gene signature for mitochondrial fitness: a potential biomarker
"Alterations in metabolism are a key feature of cancer, but molecular signatures of altered bioenergetics that aid in clinical decision-making do not currently exist," the Wistar Institute team wrote at the beginning of their publication. They identified an optimised signature of 11 genes for Mic60-deficient tumours that are expressed differently in several malignancies than in normal tissues and correlate with poor outcomes.
In the analysis of three independent patient cohorts with pancreatic ductal adenocarcinoma (PDAC), they were able to document the clinical relevance of the protein: the Mic60-poor gene signature was associated with aggressive tumour variants, local inflammation, FOLFIRINOX failure and shortened survival, regardless of age, gender or tumour stage.
Since mitochondria play a central role in cancer cell metabolism and dysfunctional mitochondria are common during tumour growth, the researchers hope that this Mic60-poor gene signature could serve as a potentially simple, easily accessible biomarker for predicting PDAC or response to therapies and help in the clinic to identify patients at higher risk for severe and progressive disease - not only in PDAC, but potentially in other cancers, including glioblastoma.
To establish, test, and validate this in a comprehensive manner, studies of larger datasets with extensive clinical information, not limited to pancreatic cancer, are planned next.3,4
Pancreatic cancer survival statistics. 2015. Cancer Research UK.
- Rahib, L., Wehner, M. R., Matrisian, L. M. & Nead, K. T. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Network Open 4, e214708 (2021).
Wistar Scientists Identify Link Between Mitochondria and Pancreatic Cancer Risk. Wistar Institute.
- Kossenkov, A. V. et al. Mitochondrial fitness and cancer risk. PLOS ONE 17, e0273520 (2022).
- Feng, Y., Madungwe, N. B. & Bopassa, J. C. Mitochondrial inner membrane protein, Mic60/mitofilin in mammalian organ protection. J Cell Physiol 234, 3383–3393 (2019).