May 2024 - Shweta Tikoo

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Dr. Shweta Tikoo

MedUni Wien RESEARCHER OF THE MONTH May 2024

The jury “Researcher of the Month” awards this month’s award to Dr. Shweta Tikoo for the publication of the manuscript “Invasion-Block and S-MARVEL: A high-content screening and image analysis platform identifies ATM kinase as a modulator of melanoma invasion and metastasis” in the top journal “Proceedings of the National Academy of Sciences” (IF 11.1). This multidisciplinary study led by Dr. Shweta Tikoo was carried out as a collaboration between The Department of Dermatology, Medical University of Vienna; Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia; and The Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer, Children’s Cancer Institute, University of New South Wales (UNSW) Sydney, Australia.

From the Stars to Cancer Therapy: Targeted Blockade of Cancer Cell Invasion through ATM-kinase-inhibitors

Metastasis represents the primary cause of cancer-associated fatalities. Despite a massive shift in the treatment landscape of malignancies in the past decade, therapeutic perturbation of the actual metastatic process is yet to be achieved. One of the key features of metastasis is the formation of invadopodia by the tumor cells. Invadopodia are F-actin-based membrane protrusions that aid in directional matrix degradation, cell migration, tumor cell dissemination, and the survival of tumor cells at secondary metastatic sites.

Our recent work focuses on the development of a novel high-content, high-throughput screening platform termed Invasion-Block for the screening of drugs that can block invadopodia-mediated matrix degradation. Coupled with a custom-developed image analysis pipeline termed S-MARVEL (Smoothen, Mask, and Reveal) adapted from astronomical sciences, this platform helped us evaluate the efficacy of 3840 FDA (Food and Drug Administration, USA) approved drugs for blocking the invasion capacity of highly metastatic melanoma cells. We found that Abl/Src, PKC, PI3K, and ATM kinase inhibitors were able to significantly reduce the invadopodia formation thereby stalling melanoma cell invasion. These results were further validated using a subsequent kinase-specific drug screen which reaffirmed ATM kinase inhibitors as a strong candidate for inhibiting invadopodia-mediated tumor cell invasion.

Finally, we validated the functionality of our leads both in vitro and in vivo utilizing ATM kinase gene knockout melanoma cells, thereby emphasizing the role ATM kinase plays in modulating the metastatic process in vivo. Collectively, our work suggests that ATM kinase may serve as a potent therapeutic target for the treatment of metastatic melanoma.

Dr. Tikoo’s scientific interests entail the study of cellular and molecular players involved in tumor development and metastasis. During her PhD at the National Institute of Immunology, New Delhi, India, Dr. Tikoo investigated the DNA damage and repair pathways crucial for maintaining genomic integrity, in particular, the role of post-translational modifications during DNA damage and repair^1,2. After receiving her PhD in 2013, Dr. Tikoo joined Prof. Wolfgang Weninger’s laboratory as a postdoctoral fellow, wherein, she was interested in understanding the role of tumor microenvironment in cancer development and metastasis, in particular, the role of perivascular macrophages³ in promoting a pro-tumoural microenvironment. Using cutting-edge immunological and sequencing technologies, Dr. Tikoo has discovered a novel myeloid precursor population that gives rise to specialized tissue-resident macrophages and has implications in designing novel therapeutics for the treatment of various solid cancers⁴. Dr. Tikoo has also discovered a hitherto undescribed site of embryonic hematopoiesis⁴. Employing a metagenomics approach, Dr. Tikoo has been instrumental in the identification of a novel virus strain responsible for causing inflammatory kidney disease⁵ and holds an international patent for the same (PCT/AU2018/050505). Furthermore, Dr. Tikoo has designed and developed various imaging modalities for improved real-time visualization of the tumor microenvironment^6,7. Dr. Tikoo is also interested in discovering novel therapeutics for the treatment of metastatic melanoma^8-10.

Selected Literature

1        Tikoo, S. et al. Ubiquitin-dependent recruitment of the Bloom syndrome helicase upon replication stress is required to suppress homologous recombination. EMBO J 32, 1778-1792 (2013). https://doi.org:10.1038/emboj.2013.117

2        Tikoo, S. & Sengupta, S. Time to bloom. Genome integrity 1, 14 (2010). https://doi.org:10.1186/2041-9414-1-14

3        Abtin, A. et al. Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat Immunol 15, 45-53 (2014). https://doi.org:10.1038/ni.2769

4        Tikoo, S. et al. A distinct CD115^- erythro-myeloid precursor present at the maternal-embryonic interface and in the bone marrow of adult mice. bioRxiv, 2021.2007.2024.453629 (2021). https://doi.org:10.1101/2021.07.24.453629

5        Roediger, B. et al. An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis. Cell 175, 530-543 e524 (2018). https://doi.org:10.1016/j.cell.2018.08.013

6        Jain, R. et al. Visualizing murine breast and melanoma tumor microenvironment using intravital multiphoton microscopy. STAR Protoc 2, 100722 (2021). https://doi.org:10.1016/j.xpro.2021.100722

7        Tikoo, S. et al. Amelanotic B16-F10 Melanoma Compatible with Advanced Three-Dimensional Imaging Modalities. J Invest Dermatol 141, 2090-2094 e2096 (2021). https://doi.org:10.1016/j.jid.2021.01.025

8        Guo, D. et al. RAB27A/Melanophilin Blocker Inhibits Melanoma Cell Motility and Invasion. J Invest Dermatol 140, 1470-1473 e1473 (2020). https://doi.org:10.1016/j.jid.2019.12.023

9        Guo, D. et al. Abrogation of RAB27A expression transiently affects melanoma cell proliferation. Pigment Cell Melanoma Res 33, 889-894 (2020). https://doi.org:10.1111/pcmr.12903

10      Guo, D. et al. Invasion-Block and S-MARVEL: A high-content screening and image analysis platform identifies ATM kinase as a modulator of melanoma invasion and metastasis. Proc Natl Acad Sci U S A 120, e2303978120 (2023). https://doi.org:10.1073/pnas.2303978120