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The role of “mitotic slippage” in the origin of amoeboid metastatic cell in therapy resistant cancers

 

 

Funding: European Regional Development Fund (ERDF) “On Implementation of Activity 1.1.1.2 “Post-doctoral Research Aid” of the Specific Aid Objective 1.1.1 “To increase the research and innovative capacity of scientific institutions of Latvia and the ability to attract external financing, investing in human resources and infrastructure” of the Operational Programme “Growth and Employment”

Project Title: The role of “mitotic slippage” in the origin of amoeboid metastatic cell in therapy resistant cancers

Project No.: 1.1.1.2/VIAA/3/19/463

Period: 36 months (1 January 2020 – 31 December 2022)

Project costs: 133 806.00 EUR

Project implementer: Dr. biol. Kristīne Salmiņa

 

The mortality of cancer patients still remains high, mostly due to metastatic disease, where tumor cell migration is a critical mechanism in development of resistance to anticancer therapy.  The amoeboid motility is a very efficient mode of migration and metastatic growth of single tumor cells. The working hypothesis of this project suggests the role of “mitotic slippage” – reverse of aborted mitosis enhanced by therapy in formation of polyploid tumour cells undergoing the reprogramming to amoeboid state. Beside motility, amoeboid cancer cells display various activities cooperatively enabling survival and drug-resistant metastatic growth. Impact of the key amoebal cdc42-kinase on these activities will be characterised in mechanistic experiments. The work will be performed on breast cancer and melanoma cell lines, and include the patient material. Genotoxic treatments, cdc42 inhibition will be examined by immunofluorescence, cytometry, western blot, qRT-PCR, live-imaging and confocal microscopy. In addition, the clonogenicity, migration, invasion, and tumorigenicity tests will be applied.

Information published 02.01.2020.

 

Project progress

 1 January 2020 – 31 March 2020

At this stage of the project, the breast cancer MDA-MB 231 cell line was treated with the anticancer agent doxorubicin, and mitotic slippage, which is the source of giant cell formation, was observed. The cell cycle, polyploidization, growth curve and microscopic counts of mitotic slippage were determined. Activation of the meiotic genes MOS, DMC1, REC8 and SPO11 after cell treatment was observed. The signs of amoeboidisation in giant cells resulting from the application of anti-cancer therapy in comparison to control cells have been investigated. Work has been done to prepare and submit the publication.

Information published 31.03.2020. 

 

Project progress

 1 April 2020 – 30 June 2020

At this stage of the project, the human melanoma SK-MEL 28 cell line was treated with the anticancer agent Vemurafenib and the cell cycle, growth curve and expression of meiotic genes after optimization of cell treatment were determined. However, increased cell polyploidisation and mitotic slippage were not observed after treatment. A scientific article on the role of mitotic slippage and extranuclear DNA in cancer cell resistance has been published: doi: 10.3390/ijms21082779.

Information published 30.06.2020. 



Mājas lapas izstrādi finansēja ERAF 2.1.1.2. aktivitātes projekts Nr. 2010/0196/2DP/2.1.1.2.0/10/APIA/VIAA/004 "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".