WNT-Conditioned Mechanism of Exit from Postchemotherapy Shock of Differentiated Tumour Cells

Irina A Tsydenova; Daria S Dolgasheva; Ksenia A Gaptulbarova; Marina K Ibragimova; Matvei M Tsyganov; Ekaterina A Kravtsova; Anna A Nushtaeva; Nikolai V Litviakov

doi:10.3390/cancers15102765

WNT-Conditioned Mechanism of Exit from Postchemotherapy Shock of Differentiated Tumour Cells

Cancers (Basel). 2023 May 15;15(10):2765. doi: 10.3390/cancers15102765.

Authors

Irina A Tsydenova^{1

2}, Daria S Dolgasheva^{1

2}, Ksenia A Gaptulbarova^{1

2

3}, Marina K Ibragimova^{1

2

3}, Matvei M Tsyganov^{1

3}, Ekaterina A Kravtsova^{1

2}, Anna A Nushtaeva⁴, Nikolai V Litviakov^{1

2

3}

Affiliations

¹ Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634028 Tomsk, Russia.
² Biological Institute, National Research Tomsk State University, 634050 Tomsk, Russia.
³ Genetic Technology Laboratory, Siberian State Medical University, 634050 Tomsk, Russia.
⁴ Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia.

Abstract

Background: the present study aims to prove or disprove the hypothesis that the state of copy number aberration (CNA) activation of WNT signalling pathway genes accounts for the ability of differentiated tumour cells to emerge from postchemotherapy shock.

Methods: In the first step, the CNA genetic landscape of breast cancer cell lines BT-474, BT-549, MDA-MB-231, MDA-MD-468, MCF7, SK-BR-3 and T47D, which were obtained from ATCC, was examined to rank cell cultures according to the degree of ectopic activation of the WNT signalling pathway. Then two lines of T47D with ectopic activation and BT-474 without activation were selected. The differentiated EpCAM+CD44-CD24-/+ cells of these lines were subjected to IL6 de-differentiation with formation of mammospheres on the background of cisplatin and WNT signalling inhibitor ICG-001.

Results: it was found that T47D cells with ectopic WNT signalling activation after cisplatin exposure were dedifferentiated to form mammospheres while BT-474 cells without ectopic WNT-signalling activation did not form mammospheres. The dedifferentiation of T47D cells after cisplatin exposure was completely suppressed by the WNT signalling inhibitor ICG-001. Separately, ICG-001 reduced, but did not abolish, the ability to dedifferentiate in both cell lines.

Conclusions: these data support the hypothesis that the emergence of differentiated tumour cells from postchemotherapy shock after chemotherapy is due to ectopic activation of WNT signalling pathway genes.

Keywords: WNT signalling pathway; breast cancer cell lines; dedifferentiation; mammospheres; metastases.

Grants and funding

075-15-2021-1073/State contract of the Ministry of Science and Higher Education of the Russian Federation "Genetic and epigenetic editing of tumor cells and microenvironment in order to block metastasis"