Division of Drug Discovery & Safety
Cancer Therapeutics and Drug Safety
In this research group, headed by Bob Van de Water, cell signaling programs that underlie adverse drug reactions as well as cancer development and progression are unraveled. Adverse drug reactions involve cell injury in critical target organ cells which leads to the activation of cellular stress response signaling pathways. We study the molecular mechanisms of cellular stress response activation and control of cell survival and cell death. In the context of cancer, we investigate the signaling networks that underlie breast cancer drug resistance and metastasis formation. The application of functional genomics and high throughput microscopy to uncover the dynamics of the signaling networks is central in both research programs.
Adverse drug reactions are a major problem in the clinic as well as for the failure of novel chemical entities during drug development. The liver and the kidney are major target organs for adverse drug reactions. In the liver, the hepatocytes are critical cells that are affected upon drug treatment; in the kidney these are the proximal tubular cells of the nephron. Cellular physiological perturbations due to drug exposure lead to the activation of adaptive stress response pathways. These involve amongst others the oxidative stress response pathway, the unfolded protein response pathway and DNA damage response pathway. Our aim is to understand the molecular mechanisms that control these adaptive stress response pathways at the single cell level. We have established fluorescent protein reporter cell lines that allow the quantitative assessment of individual components of these pathways at the single cell level using automated high throughput microscopy.
We apply functional genomics screens to unravel novel genetic components that control these pathways. Moreover, we are manipulating human induced-pluripotent stem cells (iPSCs) to integrate our fluorescent reporters and establish differentiated liver, neuronal and cardiac cells from these reporter cell lines that are then applied in dynamic cell imaging. High throughput transcriptomics is used to define the dynamics of gene activation during cellular stress responses. Bioinformatics approaches are integrated to derive imaging- and transcriptomics-based classifiers to predict liver and renal toxicity.
A second line of research is focused on the breast cancer development and progression. Breast cancer is the most common type of cancer amongst women. We aim to understand the molecular mechanisms that underlie breast cancer metastasis as well as drug resistance. Breast cancer can be differentiated in different subtypes. Triple negative breast cancer (TNBC) comprises around 15-20% of all breast cancers and is the most aggressive subtype of breast cancer with metastasis formation to different target tissues, including lung, bone and brain.
Currently, there is no targeted therapy available for TNBC and treatment mainly relies on irradiation and chemotherapeutics. We investigate the signaling components that control metastasis formation of TNBC through understanding the cell signaling components that control TNBC cell migratory behavior. We apply high throughput microscopy in combination with functional genomics strategies to identify critical modulators of TNBC cell migration. Furthermore, we study the metastasis formation in mouse models of breast cancer metastasis formation. Novel drug targets to combat TNBC are discovered through synthetic lethality screens using both functional genomics strategies as well as large compound screens.
Our focus is on kinases as well as direct modulators of RNA splicing. For luminal estrogen receptor positive breast cancer we aim to understand resistance to anti-estrogen therapy. Breast cancer cell models for our work involve both human breast cancer cell line panels as well as patient derived xenograft models. Transcriptomics is integrated in our strategies to understand the mode-of-action of candidate drug targets and drug leads.
Key publications
- Zhang Y, Wester L, He J, Geiger T, Moerkens M, Siddappa R, Helmijr JA, Timmermans MM, Look MP, van Deurzen CHM, Martens JWM, Pont C, de Graauw M, Danen EHJ, Berns EMJJ, Meerman JHN, Jansen MPHM, van de Water B. IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer. Oncogene. 2018.
- Wink S, Hiemstra S, Herpers B, van de Water B. High-content imaging-based BAC-GFP toxicity pathway reporters to assess chemical adversity liabilities. Arch Toxicol. 2017 Mar;91(3):1367-1383.
- Herpers B, Wink S, Fredriksson L, Di Z, Hendriks G, Vrieling H, de Bont H, van de Water B. Activation of the Nrf2 response by intrinsic hepatotoxic drugs correlates with suppression of NF-κB activation and sensitizes toward TNFα-induced cytotoxicity. Arch Toxicol. 2016 May;90(5):1163-79.
- van Roosmalen W, Le Dévédec SE, Golani O, Smid M, Pulyakhina I, Timmermans AM, Look MP, Zi D, Pont C, de Graauw M, Naffar-Abu-Amara S, Kirsanova C, Rustici G, Hoen PA, Martens JW, Foekens JA, Geiger B, van de Water B. Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant. J Clin Invest. 2015 Apr;125(4):1648-64.
- de Graauw M, van Miltenburg MH, Schmidt MK, Pont C, Lalai R, Kartopawiro J, Pardali E, Le Dévédec SE, Smit VT, van der Wal A, Van't Veer LJ, Cleton-Jansen AM, ten Dijke P, van de Water B. Annexin A1 regulates TGF-beta signaling and promotes metastasis formation of basal-like breast cancer cells. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6340-5.