Role of microRNAs in Driving Breast and Lung Cancer Metastases Identified Interview with:

Dr Olivier E Pardo PhD Team Leader Imperial College Division of Cancer Hammersmith Hospital London UK

Dr. Olivier Pardo

Dr Olivier E Pardo PhD
Team Leader
Imperial College
Division of Cancer
Hammersmith Hospital
London UK What is the background for this study? What are the main findings?

Dr. Pardo: Metastatic dissemination, the ability of tumour cells to go and colonise organs distant from the primary disease site, is the principal cause for failing to cure patients with cancer. This is particularly true in the case of breast cancer where resection of local disease offers good chances of cure but metastatic dissemination that may appear at a later stage carries very poor prognosis. Surgical resection is also the only true curative strategy for localised lung cancer. Hence, a better understanding of the mechanisms controlling the dissemination of tumour cells is likely to propose novel targets for combination therapy that will improve the survival of cancer patients.

Here, we showed that an enzyme, named MARK4, controls the ability of lung and breast cancer cells to move and invade. When we lower MARK4 levels, it prevents cancer cells from moving by changing their internal architecture, making them unfit to invade. Consequently, these cells were unable to efficiently form metastasis in mouse cancer models. Confirming the role of this enzyme in cancer, we show that breast and lung cancer patients with increased levels of MARK4 in their tumours have poorer prognosis.

We found that what controls the levels of MARK4 in cells is miR-515-5p, a small oligonucleotide sequence called a microRNA. When present in the cells, miR-515-5p prevents the expression of MARK4. Incidentally, the loss of miR-515-5p correlates with increased metastasis and poorer prognosis in mouse cancer models and patients, respectively. What should clinicians and patients take away from your report?

Dr. Pardo: MARK4 is a member of the MARK family of proteins. These have been involved in dementia such as Alzheimer disease and inhibitors for these enzymes are actively being developed as possible therapeutic agents for these pathologies. Our results suggest that these drugs may also represent interesting agents to prevent the dissemination of cancer in patients that are being treated for localised disease. What recommendations do you have for future research as a result of this study?

Dr. Pardo: MARK4 inhibitors need to be tested in cancer models to assess whether they can efficiently prevent tumour metastasis. Our data also show that the same changes to the cell’s internal architecture that occur following decreased MARK4 expression prevent the cells from efficiently dividing. Therefore, there is a chance that these drugs may also be able to control cancer growth. Is there anything else you would like to add?

Dr. Pardo: This study highlights once more the central role of microRNAs in controlling multiple aspects of cancer biology. A better understanding of what regulates the expression of these small oligonucleotide sequences may yield novel therapeutic strategies with profound implications for the treatment of cancer. Which is why funding such as the one we received from the NIHR, the MRC, the Cancer Treatment and Research Trust (CTRT), Action Against Cancer and the Hilary craft foundation to perform this work is so important.

This work is dedicated to the memory of Colin James McDavid. Thank you for your contribution to the community.



EMBO Rep. 2016 Feb 10. pii: e201540970. [Epub ahead of print]

miR-515-5p controls cancer cell migration through MARK4 regulation.

Pardo OE1, Castellano L2, Munro CE2, Hu Y3, Mauri F2, Krell J2, Lara R2, Pinho FG2, Choudhury T2, Frampton AE2, Pellegrino L2, Pshezhetskiy D2, Wang Y3, Waxman J2, Seckl MJ4, Stebbing J4.

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Dr Olivier E Pardo (2016). Role of microRNAs in Driving Breast and Lung Cancer Metastases Identified