Zdenek Andrysik: Molecular Mechanisms of Cancer


About our research


To identify innovative treatment opportunities represented by targeting transcription factors (TFs) involved in carcinogenesis.


To save lives of people with cancer by designing a novel, combinatorial, and targeted treatment strategies utilizing TF activity modulation.

Reseach Philosophy

Cancer is the most complex and complicated medical challenge mankind faces today and the leading cause of premature death in 57 most developed countries including Czech Republic1. Due to cancer our society loses an enormous amount of experience, performance, and talent every year since about half of the cancer deaths concerns economically active people2. Czechs have ~30% chance of developing a cancer before 75 years of age3. Despite of tremendous advance in life expectancy of patients diagnosed with cancer over the last decades, more than 27 000 people die of cancer in Czech Republic annually3. Furthermore, current chemotherapy is linked to a broad range of adverse effects including lasting cognitive impairment4 and secondary cancer5-9. Therefore, novel treatment strategies based on thorough understanding of molecular mechanisms of the disease are essential for improving survivability and quality of life of patients diagnosed with cancer.

Cancer occurs from genetic and epigenetic alterations resulting in deregulated transcriptional programs10, which are associated with virtually all hallmarks of cancer11. Aberrant activity of TFs constitutes cancer dependency and earmarks TFs as targets in the treatment of particular malignancies, such as cancers dependent on nuclear hormone receptors12. Acting both as oncogenes and tumor suppressors, TFs are no longer considered as “undruggable”13,14 as ever-increasing portfolio of compounds is available for research and treatment applications while novel technologies increase drug specificity15. Taken together, TFs represent a prime target for designing innovative treatment strategies and facilitating personalized medicine.

Reseach Areas

TP53 – a mighty ally in our fight against cancer

“It’s a machine gun in the world of peashooters.” Jo Nesbø, Headhunters, 2011

TP53 is the most frequently mutated tumor suppressor gene in our genome. Protein product of the TP53 gene, TF p53 regulates expression of hundreds of genes which in a concert mediate the tumor suppressive functions of TP5316. It is no surprise that TP53 is the most often studied gene ever17. Some say that it is the 20 copies of TP53 gene what keeps elephants alive for about 65 years without notable incidence of cancer in their large bodies18. Others see p53 nuclear accumulation as a prerequisite of African naked mole-rat longevity19, since these small critters live for 30 years, six times longer than other rodents on average. Moreover, by 2024 we have drugs which very specifically activate p53 for 20 years20. And yet, we don’t have a viable strategy for using p53 activation in targeted cancer treatment.

Activated by various kinds of cellular stress, p53 controls several cellular programs constraining cancer progression including cell cycle arrest, senescence, and apoptosis21(Fig.1). However, targeted activation of p53 by small molecule inhibitors of its endogenous repressor MDM2 results in a reversible cell cycle arrest response in most cancer cell types, which may explain the limited therapeutic value of these drugs so far22.

Recently, Dr. Andrysik published a novel treatment strategy augmenting the p53 response to the level required for apoptosis initiation23. Simultaneous induction of p53 and Integrated Stress Response leads to cancer cell elimination in vitro and arrested tumor growth in vivo (Fig.2). This discovery opens the door to both mechanistic studies elucidating underpinnings of the p53-dependent apoptosis and translational-medicine oriented works improving efficacy this promising treatment approach in vivo.

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Figure 1. Upon activation by numerous stress stimuli, p53 activates transcription of a broad range of genes involved in tumor suppression. Apoptosis represents the desired outcome of p53 induction in cancer therapy.

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Figure 2. (A) Joint activation of p53 by MDM2 inhibitor nutlin and ISR by nelfinavir leads to strong apoptotic response in vitro. (B) Milademetan, a MDM2 inhibitor designed for use in vivo, in combination with nelfinavir extends significantly life of animals with xenograft tumors(Andrysik, 2022).

Hypoxia and p53 – when two do the same thing, it is not the same thing after all

Low levels of oxygen tension are characteristic to majority of solid tumors growing in size. Hypoxia stimulates adaptive changes in metabolism and contributes to therapy resistance24 Our scRNA-seq analysis in tumors as well as mapping of transcriptomes regulated by p53 and hypoxia showed that both networks overlap at genes associated with cell cycle arrest23,25 (Fig. 3). Elucidation of the p53 and hypoxia crosstalk is critical for designing an effective therapy based on targeted induction of the tumor suppressor p53.

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Figure 3. (A) Both hypoxia and p53 induce substantial changes in cellular transcriptome measured here by RNA-seq. (B) p53 and hypoxia regulatory networks intersect through indirect/secondary mechanisms. (C) scRNA-seq in tumor tissue allows scoring clusters for both hypoxia and p53 activities.


1 Bray, F., Laversanne, M., Weiderpass, E. & Soerjomataram, I. The ever-increasing importance of cancer as a leading cause of premature death worldwide. Cancer 127, 3029-3030 (2021). https://doi.org/10.1002/cncr.33587

2 Ritchie, M. R. a. H. Cancer, <https://ourworldindata.org/cancer> (2019).

3 Dusek, L. et al. Cancer incidence and mortality in the Czech Republic. Klin Onkol 27, 406-423 (2014). https://doi.org/10.14735/amko2014406

4 Das, A. et al. An Overview on Chemotherapy-induced Cognitive Impairment and Potential Role of Antidepressants. Curr Neuropharmacol 18, 838-851 (2020). https://doi.org/10.2174/1570159X18666200221113842

5 Boffetta, P. & Kaldor, J. M. Secondary malignancies following cancer chemotherapy. Acta Oncol 33, 591-598 (1994). https://doi.org/10.3109/02841869409121767

6 Vega-Stromberg, T. Chemotherapy-induced secondary malignancies. J Infus Nurs 26, 353-361 (2003). https://doi.org/10.1097/00129804-200311000-00004

7 Rubino, C., de Vathaire, F., Shamsaldin, A., Labbe, M. & Le, M. G. Radiation dose, chemotherapy, hormonal treatment and risk of second cancer after breast cancer treatment. Br J Cancer 89, 840-846 (2003). https://doi.org/10.1038/sj.bjc.6601138

8 Temming, P. et al. Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center. Pediatr Blood Cancer 64, 71-80 (2017). https://doi.org/10.1002/pbc.26193

9 Travis, L. B. et al. Risk of leukemia after platinum-based chemotherapy for ovarian cancer. N Engl J Med 340, 351-357 (1999). https://doi.org/10.1056/NEJM199902043400504

10 Bradner, J. E., Hnisz, D. & Young, R. A. Transcriptional Addiction in Cancer. Cell 168, 629-643 (2017). https://doi.org/10.1016/j.cell.2016.12.013

11 Hanahan, D. Hallmarks of Cancer: New Dimensions. Cancer Discov 12, 31-46 (2022). https://doi.org/10.1158/2159-8290.CD-21-1059

12 Bhagwat, A. S. & Vakoc, C. R. Targeting Transcription Factors in Cancer. Trends Cancer 1, 53-65 (2015). https://doi.org/10.1016/j.trecan.2015.07.001

13 Henley, M. J. & Koehler, A. N. Advances in targeting 'undruggable' transcription factors with small molecules. Nat Rev Drug Discov 20, 669-688 (2021). https://doi.org/10.1038/s41573-021-00199-0

14 Tao, Z. & Wu, X. Targeting Transcription Factors in Cancer: From "Undruggable" to "Druggable". Methods Mol Biol 2594, 107-131 (2023). https://doi.org/10.1007/978-1-0716-2815-7_9

15 Li, Y., Song, J., Zhou, P., Zhou, J. & Xie, S. Targeting Undruggable Transcription Factors with PROTACs: Advances and Perspectives. J Med Chem 65, 10183-10194 (2022). https://doi.org/10.1021/acs.jmedchem.2c00691

16 Andrysik, Z. et al. Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity. Genome Res 27, 1645-1657 (2017). https://doi.org/10.1101/gr.220533.117

17 Gates, A. J., Gysi, D. M., Kellis, M. & Barabasi, A. L. A wealth of discovery built on the Human Genome Project - by the numbers. Nature 590, 212-215 (2021). https://doi.org/10.1038/d41586-021-00314-6

18 Bartas, M. et al. The Changes in the p53 Protein across the Animal Kingdom Point to Its Involvement in Longevity. Int J Mol Sci 22 (2021). https://doi.org/10.3390/ijms22168512

19 Deuker, M. M. et al. Unprovoked Stabilization and Nuclear Accumulation of the Naked Mole-Rat p53 Protein. Sci Rep 10, 6966 (2020). https://doi.org/10.1038/s41598-020-64009-0

20 Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848 (2004). https://doi.org/10.1126/science.1092472

21 Vousden, K. H. & Prives, C. Blinded by the Light: The Growing Complexity of p53. Cell 137, 413-431 (2009). https://doi.org/10.1016/j.cell.2009.04.037

22 Tovar, C. et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A 103, 1888-1893 (2006). https://doi.org/10.1073/pnas.0507493103

23 Andrysik, Z., Sullivan, K. D., Kieft, J. S. & Espinosa, J. M. PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response. Nat Commun 13, 7400 (2022). https://doi.org/10.1038/s41467-022-35089-5

24 Muz, B., de la Puente, P., Azab, F. & Azab, A. K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia (Auckl) 3, 83-92 (2015). https://doi.org/10.2147/HP.S93413

25 Andrysik, Z., Bender, H., Galbraith, M. D. & Espinosa, J. M. Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response. Nat Commun 12, 1375 (2021). https://doi.org/10.1038/s41467-021-21687-2


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