Lajos MÁTÉS
senior research associate

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Andrea NAGY research associate
András BLASTYÁK research associate
Kata RADVÁNSZKINÉ DR. MIKULÁSS research associate
Dávid PUSZTAI junior research associate
Liza HUDOBA scientific administrator
Gergely IMRE Ph.D. student
Anna FARAGÓ Ph.D. student
Andrea BAKNÉ DRUBI Ph.D. student
Ildikó FEKETE laboratory assistant
Erzsébet FEHÉRNÉ JUHÁSZ scientific administrator

THE “MUTATOR” PHENOTYPE OF CANCER

Cancer is the leading cause of death in the developed world. According to estimates from the International Agency for Research on Cancer, there were 7.6 million cancer deaths in 2008 worldwide, and by 2030 the global burden is expected to grow to 13.2 million deaths simply due to the growth and aging of the population.

Cancer development can be considered as an evolutionary process within our body. In 1976, Nowell synthesized the evolutionary view of cancer as a process of genetic instability generating the genetic variations and natural selection analogous to Darwinian evolution. According to this theory, most of the alterations that occur in the genome of a cell are deleterious or do not confer a growth advantage to the cell, and such clones will tend to go extinct, but occasionally, selectively advantageous mutations arise that lead to clonal expansion. The theory predicts a unique genetic composition in each neoplasm due to the random process of mutations. The recent progress of instrumentation in molecular biology and the development of related fields like stem cell biology have made a seminal impact on cancer research. The newer data led us to realize the fact that tumors are heterogeneous; the cells in a tumor vary by phenotype. One of the most important consequences of this finding was the introduction of the “Cancer Stem Cell” theory, which further refined our concept of cancer. Cancer stem cells (CSCs), also referred to as tumor-initiating cells (TICs), are cells that are capable of self-renewal and of producing a new tumor with the same heterogeneity that is characteristic of the parental tumor. For a while, it seemed that CSCs are the key cell populations in cancer therapy. However, according to the testimony of more recent studies, in tumors, CSCs and partially differentiated cancer cell populations can most probably convert into each other. The most important implication of these new results is that the de novo generation of cancer stem cells suggests that simply targeting a cancer stem cell population will not necessarily prevent tumor recurrence.




Figure 1. Outline of cancer development

More recently, by integrating the mass of new data accumulated in cancer research, Hanahan and Weinberg refined Nowell’s view on the malignant process and suggested that all cancers can be described by a small number of underlying biological principles describing how tumor progression proceeds. These “hallmarks” of cancer comprise distinct biological capabilities acquired during the multistep development of tumors (Fig 1.). This refined view better reflects the large quantities of unique “passenger” mutations (not shown) and the smaller number of more common “driver” mutations (Fig 1.) found in cancers since “driver“ mutations probably affect a limited number of genes that are functionally related to the “hallmark” capabilities. Notably, many of the early “hallmarks” are shared with adult tissue resident stem cells highlighting this cell population as a potential target of malignant transformation. Underlying the “hallmarks”, there are cellular and supracellular facilitating factors like genome instability, which generates the genetic diversity that expedites their acquisition (Fig 1.). It was also proposed long ago that the spontaneous mutation rate in normal cells is not sufficient to account for the high total number of mutations found in cancers further highlighting the relevance of genome instability. This so-called “mutator” phenotype of cancer cells develops in response to “mutator” mutations (Fig 1.) affecting genes that function in the maintenance of genome integrity causing a varying degree of genome instability. It is supported by numerous examples that errors in DNA repair processes serve as engines for such a “mutator” phenotype. In addition, recent findings emphasize the role of genomic instability in cancer caused also by diverse errors leading to chromosomal instability, and alterations of epigenetic mechanisms leading to changes in gene expression.

The long-term objective of our laboratory is to explore cellular events fuelling malignant transformation by undermining genome integrity. We plan to identify and investigate new “mutator” alleles using animal models and state-of-the-art gene transfer technologies.

Selected publications

Katter, K., Geurts, A.M., Hoffmann, O., Mátés, L., Landa, V., Hiripi, L., Moreno, C., Lazar, J., Bashir, S., Zideke, V., Popova, E., Jerchowc, B., Beckerc, K., Devarajc, A., Walterj, I., Grzybowksib, M., Corbettb, M., Filhol, A.R., Hodgesb, M.R., Baderc, M., Ivics, Z., Jacob, H.J., Pravenec, M., Bősze, Z., Rülicke, T. and Izsvák, Z. Transposon-mediated Transgenesis, Transgenic Rescue, and Tissue-specific Gene Expression in Rodents and Rabbit. FASEB J 27: (3)930-941 (2013)

Xue, X., Huang, X., Nodland, S.E., Mates, L., Ma, L., Izsvak, Z., Ivics, Z., LeBien, T.W., McIvor, R.S., Wagner, J.E., and Zhou, X. Stable gene transfer and expression in cord blood-derived CD34+ hematopoietic stem and progenitor cells by a hyperactive Sleeping Beauty transposon system. (2009), Blood 114(7): 1319-1330.

Mates, L., Chuah, M.K., Belay, E., Jerchow, B., Manoj, N., Acosta-Sanchez, A., Grzela, D.P., Schmitt, A., Becker, K., Matrai, J., Ma, L., Samara-Kuko, E., Gysemans, C., Pryputniewicz, D., Miskey, C., Fletcher, B., VandenDriessche, T., Ivics, Z., and Izsvak, Z. Molecular evolution of a novel hyperactive Sleeping Beauty transposase enables robust stable gene transfer in vertebrates. (2009), Nat Genet 41(6): 753-761.

Ivics, Z., Li, M.A., Mates, L., Boeke, J.D., Nagy, A., Bradley, A., and Izsvak, Z. Transposon-mediated genome manipulation in vertebrates. (2009), Nat Methods 6(6): 415-422.

Mates, L., Izsvak, Z., and Ivics, Z. Technology transfer from worms and flies to vertebrates: transposition-based genome manipulations and their future perspectives. (2007), Genome Biol 8 Suppl 1: S1.