The role of nuclear Piezo1 in neoplastic proliferation

Primary supervisor: Jody Rosenblatt, King’s College London

Secondary supervisor: Silvia Santos, Francis Crick Institute

Project

Background: Most solid tumours originate from epithelial cells that lose control over their growth, leading to excessive, dysfunctional cell proliferation. Conventional cancer treatments often target these proliferation mechanisms. However, recent studies suggest that cancer growth may resemble the body’s wound healing process, where cells rapidly divide in response to tissue damage. This response can be triggered not only by genetic mutations but also by external factors such as smoking, pollution, viral infections, and chronic inflammation.

Our lab and others have found that cancer cells may use a mechanical pathway to proliferate, one that mirrors the wound healing response. This pathway is mediated by Piezo1, a stretch-activated ion channel, which we have previously shown to drive cell division in response to mechanical stretch. Interestingly, this same pathway may not be affected by the drugs typically used to block cell proliferation in cancer therapeutics, making it a potential target for novel cancer therapies.

Project Description: We recently discovered that Piezo1, while typically located in the cell membrane, also translocates in the nucleus of rapidly dividing cells. We hypothesise that Piezo1-related peptides may enter the nucleus and regulate gene expression, influencing cancer cell proliferation. Understanding this novel mechanism could open up new avenues for targeting cancer cells while sparing normal tissues.

Research Plan: To test our hypothesis, the project will be structured to systematically explore the role of Piezo1 in cancer proliferation and tissue regeneration. We will first focus on identifying specific Piezo1-related peptides that accumulate in the nucleus during cell proliferation. We will then investigate whether inhibiting the formation of these peptides impacts cell division.

In the next phase, we will examine the molecular interactions of Piezo1-related peptides within the nucleus, including their binding partners and potential regulatory roles. Advanced techniques, such as ChIP-Seq-SICAP (ChIP-Seq followed by Proteomics), will be used to study how these interactions may influence gene expression. Finally, we will assess the functional significance of Piezo1 in both cancerous and regenerative tissues, providing a broader understanding of its role in tumour growth and tissue regeneration.

Key Research Aims:

1. Identify Piezo1-related peptides that accumulate in the nucleus during cell proliferation.
2. Test whether preventing Piezo1 translocation inhibits cancer cell proliferation and alters gene expression.
3. Determine nuclear binding partners and transcriptional targets.
4. Investigate the role of Piezo1 in both tissue regeneration and cancer growth

What You’ll Gain: This project offers an exciting opportunity to explore ground-breaking research in cancer cell biology. The selected PhD candidate will develop interdisciplinary skills in molecular biology, biochemistry, and advanced imaging, while contributing to cutting-edge discoveries in the field. You will work in a dynamic and diverse research environment, gaining experience in innovative cancer research that has the potential to influence future therapeutic strategies.

Candidate background

We are seeking a candidate with a strong interest in cancer biology and molecular mechanisms. While prior experience in biochemistry, molecular biology, or imaging would be beneficial, enthusiasm and a willingness to learn are the most important qualifications.

Potential Research Placements

1. Silvia Santos, Francis Crick Institute
2. TBC: To learn about cancer pathways
3. TBC: To learn about transcriptional regulation

References

1. KRas-transformed epithelia cells invade and partially dedifferentiate by basal cell extrusion. Fadul J, Zulueta-Coarasa T, Slattum GM, Redd NM, Jin MF, Redd MJ, Daetwyler S, Hedeen D, Huisken J, Rosenblatt J. Nat Commun. 2021 Dec 10;12(1):7180. doi: 10.1038/s41467-021-27513-z. PMID: 34893591.
2. Physical confinement promotes mesenchymal trans-differentiation of invading transformed cells in vivo Zulueta-Coarasa, T., Fadul, J., Ahmed, M. & Rosenblatt, J., 18 Nov 2022, In: iScience. 25, 11, 105330.Yaganoglu, S., Kalyviotis, K., Vagena-Pantoula, C. et al.
3. Mechanical stretch triggers rapid epithelial cell division through Piezo1. Gudipaty SA, Lindblom J, Loftus PD, Redd MJ, Edes K, Davey CF, Krishnegowda V, Rosenblatt J. Nature. 2017 Mar 2;543(7643):118-121. doi: 10.1038/nature21407. Epub 2017 Feb 15. PMID: 28199303.
4. Piezo1 activates noncanonical EGFR endocytosis and signaling. Pardo-Pastor C, Rosenblatt J. Sci Adv.2023 Sep 27; 9(39). doi: 10.1126/sciadv.adi1328. PMID: 37756411.
5. Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi. Yaganoglu, S., Kalyviotis, K., Vagena-Pantoula, C. et al. Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi. Nat Commun 14, 4352 (2023). https://doi.org/10.1038/s41467-023-40134-y