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Ninel Miriam Vainshelbaum is a 2nd year PhD student at the University of Latvia’s Faculty of Biology and the recipient of the University of Latvia Foundation’s Scholarship for PhD Students in the Natural, Medical and Life Sciences. She is working on her thesis research at the Latvian Biomedical Research and Study Centre’s Cancer Cell Biology and Melanoma lab under the guidance of Dr. habil. med. Jekaterina Ērenpreisa.
In late 2020 the results of a collaboration between LBMC scientists and international colleagues were published in the International Journal of Molecular Sciences as the cancer research article “Phylostratic Shift of Whole-Genome Duplications in Normal Mammalian Tissues towards Unicellularity Is Driven by Developmental Bivalent Genes and Reveals a Link to Cancer”, with Ninel co-authoring the publication.
The article represents a bioinformatics research project involving the comparison of gene expression between polyploid (containing more than 2 chromosome sets) and diploid (containing 2 chromosome sets) normal human and mouse tissues (the liver and the heart), or cross-species differential gene expression analysis. The differentially expressed genes (DEGs) were analyzed further with a variety of bioinformatic, statistical and systems biology methods to determine which molecular signaling pathways and biological processes undergo activity and interaction changes upon ploidy increase. Ninel’s contribution to the project mainly focused on the study of bivalent genes and their evolutionary phylostrata.
Ninel Miriam Vainshelbaum’s PhD thesis research is dedicated to studying ploidy alterations in malignant tumors (in particular, triploidy, which has been associated with heightened disease aggressiveness, therapy resistance and patient mortality). As such, the reader may wonder how this project involving normal, non-malignant polyploid tissue may be connected to cancer.
Cancer cells, especially those of high-grade, metastatic tumors, possess a unique capacity for rapid evolutionary adaptation which allows the disease to return after treatment. When, for example, chemotherapy and/or radiotherapy is used, a small population of cancer cells often adapts, survives, and regrows the tumor. Recent findings indicate that these adaptations involve polyploidy, the acquisition of a stem cell-like phenotype, pseudo-meiosis ( a process resembling that of sexual and asexual reproduction), as well as atavistic regression (the repression of multicellular organism genes and ancient unicellular lifeform gene activation).
By comparing normal diploid tissues with polyploid ones, the researchers have observed that polyploid cells express a significantly greater number of evolutionarily ancient (unicellular and early metazoan) genes, while genes exclusive to more recently evolved lifeforms are suppressed. Furthermore, many of the polyploidy-upregulated ancient genes have been revealed to be bivalent and involved in developmental processes. Bivalency is the presence of both activating and repressive chromatin modifications, which enables the gene to rapidly switch its activity and consequently the cell’s fate (phenotype). In addition, although the analyzed polyploid tissues were completely non-cancerous, proto-oncogenes were revealed to be upregulated, and tumor suppressor genes – repressed.
These findings are of considerable importance, as they indicate that polyploidy plays a crucial role in cancer’s ability to resist therapy and evade elimination – even in completely normal tissues, unaffected by the genomic instability and widespread mutations observed in malignant tumors, polyploidy creates genetic and epigenetic conditions that are evolutionarily advantageous for cancer evolution and therapy resistance. Moreover, the observation that the expression of bivalent genes which interact with the c-myc proto-oncogene (a major driver of cell reprogramming) shifts the transcriptome of normal polyploid tissues towards earlier evolutionary phylostrata (unicellulars) indicates that this process is likely involved in the atavistic regression and epigenetic reprogramming of malignant tumors.
Taking these fascinating findings into account, further research is currently being conducted, comparing gene expression between malignant tumor samples from “The Cancer Genome Atlas” (TCGA) database (13 tumor types overall) and matched normal samples and trying to integrate the results of the normal polyploid tissue analysis with the findings regarding pseudo-meiotic processes in cancer. There is a possibility that the obtained DEGs and the protein-protein interaction networks of their protein products have a high diagnostic and/or prognostic value which could prove useful in the struggle against therapy resistance in cancer.
The scholarship for PhD students in the natural, medical and life sciences administered by the University of Latvia Foundation helps Ninel greatly in her studies. The financial support provided by the scholarship has granted her ample opportunities to continuously improve her knowledge and skills. She has supplemented her biology education with a number of bioinformatics courses, including the EMBL-EBI Cancer Genomics course, and has recently enrolled in an online systems biology class administered by the Icahn School of Medicine at Mount Sinai in order to take her TCGA data analysis project to the next level. The scholarship also serves as a great productivity booster for the young researcher (she has co-authored three publications since obtaining it). In her opinion, it’s absolutely crucial to provide ample support to young researchers in Latvia because the difficulties caused by a lack of proper funding (for example, having to combine PhD studies with an unrelated job) are greatly detrimental to the motivation, passion and creativity that the pursuit of new scientific knowledge requires.
