Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics

Sotgia, Federica; Fiorillo, Marco; Lisanti, Michael P.

doi:10.18632/oncotarget.19612

Cited by 60 publications

(53 citation statements)

References 24 publications

(23 reference statements)

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“…Importantly, this approach effectively predicted tamoxifen-resistance in ER(+) breast cancer patients (Figure 10), as well as Taxol- and Platin-resistance in ovarian cancer patients (Figure 11) [32,33]. These results are functionally supported by further experimental observations demonstrating that Tamoxifen-resistant MCF7 cells (TAMR) show a significant increase in mitochondrial oxygen consumption and ATP production [35].…”

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 76%

“…Patients with high levels of mitochondrial markers (“bad prognosis”) could be treated with mitochondrial-based therapies, as an add-on to the standard of care, in order to effectively prevent tumor recurrence, metastasis and drug-resistance. Modified from [32,33]. …”

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

“…To test this hypothesis, we used an online survival-analysis tool (known as the KM-plotter; http://kmplot.com/analysis/) to perform Kaplan-Meier (K-M) studies on > 400 nuclear mitochondrial gene transcripts, to interrogate publically available microarray data from patients with four distinct epithelial cancer types: i) breast, ii) ovarian, iii) lung and iv) gastric [32,33]. This approach allowed us to directly perform in silico validation of these potential mitochondrial biomarkers [33,34].…”

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

“…This approach allowed us to directly perform in silico validation of these potential mitochondrial biomarkers [33,34]. …”

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

“…These patients with serous ovarian cancer had at least 5-years of follow-up data. Reproduced with permission from [33].…”

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

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A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

et al. 2018

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Here, we wish to propose a new systematic approach to cancer therapy, based on the targeting of mitochondrial metabolism, especially in cancer stem cells (CSCs). In the future, we envision that anti-mitochondrial therapy would ultimately be practiced as an add-on to more conventional therapy, largely for the prevention of tumor recurrence and cancer metastasis. This mitochondrial based oncology platform would require a panel of FDA-approved therapeutics (e.g. Doxycycline) that can safely be used to inhibit mitochondrial OXPHOS and/or biogenesis in CSCs. In addition, new therapeutics that target mitochondria could also be developed, to optimize their ability to eradicate CSCs. Finally, in this context, mitochondrial-based biomarkers (i.e. “Mito-signatures”) could be utilized as companion diagnostics, to identify high-risk cancer patients at diagnosis, facilitating the early detection of tumor recurrence and the prevention of treatment failure. In summary, we suggest that new clinical trials are warranted to test and possibly implement this emerging treatment strategy, in a variety of human cancer types. This general approach, using FDA-approved antibiotics to target mitochondria, was effective in killing CSCs originating from many different cancer types, including DCIS, breast (ER(+) and ER(-)), prostate, ovarian, lung and pancreatic cancers, as well as melanoma and glioblastoma, among others. Thus, we propose the term MITO-ONC-RX, to describe this anti-mitochondrial platform for targeting CSCs. The use of re-purposed FDA-approved drugs will undoubtedly help to accelerate the clinical evaluation of this approach, as these drugs can move directly into Phase II clinical trials, saving considerable amounts of time (10–15 y) and billions in financial resources.

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Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 76%

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

“…This approach allowed us to directly perform in silico validation of these potential mitochondrial biomarkers [33,34]. …”

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

“…These patients with serous ovarian cancer had at least 5-years of follow-up data. Reproduced with permission from [33].…”

Section: Mitochondrial-based Companion Diagnostics: Treatment Stratifmentioning

confidence: 99%

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A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

et al. 2018

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Diabetes‐mediated promotion of colon mucosa carcinogenesis is associated with mitochondrial dysfunction

et al. 2019

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Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of cancer, including colon cancer (CC). However, we recently reported no influence of T2DM on CC prognosis, suggesting that any effect might be at the early stages of tumor development. We hypothesized that T2DM may create an environment in the healthy tissue, which acts as a carcinogenesis driver in agreement with the field of cancerization concept. Here, we focused on early carcinogenesis by analyzing paired tumor and normal colonic mucosa samples from the same patients. The proteome of CC and paired mucosa was quantitatively analyzed in 28 individuals (12 diabetics and 16 nondiabetics) by mass spectrometry with isobaric labeling. Out of 3076 identified proteins, 425 were differentially expressed at the tumor in diabetics compared with nondiabetics. In the adjacent mucosa, 143 proteins were differentially expressed in diabetics and nondiabetics. An enrichment analysis of this signature pointed to mitochondria, ribosome, and translation. Only six proteins were upregulated by diabetes both in tumor and mucosa, of which five were mitochondrial proteins. Differential expression in diabetic versus nondiabetic mucosa was confirmed for MRPL53, MRPL18, and TIMM8B. Higher levels of MRPL18, TIMM8B, and EIF1A were also found in normal colon epithelial cells exposed to high‐glucose conditions. We conclude that T2DM is associated with specific molecular changes in the normal mucosa of CC patients, consistent with field of cancerization in a diabetic environment. The mitochondrial protein signature identifies a potential therapeutic target that could underlie the higher risk of CC in diabetics.

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MRPL15 is a novel prognostic biomarker and therapeutic target for epithelial ovarian cancer

Zou

et al. 2021

Cancer Medicine

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PurposeTo analyze the role of six human epididymis protein 4 (HE4)‐related mitochondrial ribosomal proteins (MRPs) in ovarian cancer and selected MRPL15, which is most closely related to the tumorigenesis and prognosis of ovarian cancer, for further analyses.MethodsUsing STRING database and MCODE plugin in Cytoscape, six MRPs were identified among genes that are upregulated in response to HE4 overexpression in epithelial ovarian cancer cells. The Cancer Genome Atlas (TCGA) ovarian cancer, GTEX, Oncomine, and TISIDB were used to analyze the expression of the six MRPs. The prognostic impact and genetic variation of these six MRPs in ovarian cancer were evaluated using Kaplan‐Meier Plotter and cBioPortal, respectively. MRPL15 was selected for immunohistochemistry and GEO verification. TCGA ovarian cancer data, gene set enrichment analysis, and Enrichr were used to explore the mechanism of MRPL15 in ovarian cancer. Finally, the relationship between MRPL15 expression and immune subtype, tumor‐infiltrating lymphocytes, and immune regulatory factors was analyzed using TCGA ovarian cancer data and TISIDB.ResultsSix MRPs (MRPL10, MRPL15, MRPL36, MRPL39, MRPS16, and MRPS31) related to HE4 in ovarian cancer were selected. MRPL15 was highly expressed and amplified in ovarian cancer and was related to the poor prognosis of patients. Mechanism analysis indicated that MRPL15 plays a role in ovarian cancer through pathways such as the cell cycle, DNA repair, and mTOR 1 signaling. High expression of MRPL15 in ovarian cancer may be associated with its amplification and hypomethylation. Additionally, MRPL15 showed the lowest expression in C3 ovarian cancer and was correlated with proliferation of CD8+ T cells and dendritic cells as well as TGFβR1 and IDO1 expression.ConclusionMRPL15 may be a prognostic indicator and therapeutic target for ovarian cancer. Because of its close correlation with HE4, this study provides insights into the mechanism of HE4 in ovarian cancer.

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Mitochondrial markers predict recurrence, metastasis and tamoxifen-resistance in breast cancer patients: Early detection of treatment failure with companion diagnostics

Cited by 60 publications

References 24 publications

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

Diabetes‐mediated promotion of colon mucosa carcinogenesis is associated with mitochondrial dysfunction

MRPL15 is a novel prognostic biomarker and therapeutic target for epithelial ovarian cancer

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