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Institute of Molecular Cancer Research Lopes Lab

  • Rapid cell division cycles accompanied with exceptionally fast DNA replication in embryonic stem cells (ESCs), impose replication stress on these cells fundamental for embryonic development. To prevent chromosomal breakage and ultimately protect their integrity, ESCs rely on extensive replication fork remodeling, whereas in their differentiated counterparts, prolonged gap phases rapidly resolve signs of replication stress (from Ahuja et al., Nature Comms 2016).

  • Comet assays reveal extensive chromosomal breakage in a subset (white arrows) of typically quiescent blood and immune stem cells, when proliferation is induced by a simulated viral infection.

  • Immunohistochemical staining of a mouse liver section with a classical mitotic marker (PHH3, brown) allows monitoring extensive hyper-proliferation induced by partial hepatectomy in this otherwise quiescent tissue.

  • Hepatocytes can be isolated from the mouse liver and used for our single-cell and single-molecule assays. This allows investigating the replication process and revealing potential marks of replicative stress in clinically relevant conditions of liver hyper-proliferation.

Replication stress in stem cells and tissues

Background

Certain cell types and tissues are intrinsically more prone to replication stress, as they are associated with constitutive or inducible hyperproliferation. This requires cell division – and thus also full genome duplication – to occur repeatedly and accurately within a particularly short time. Besides its physiological relevance, hyperproliferation is also observed in precancerous lesions as a typical feature of tumorigenesis in many different tissues. Understanding the molecular mechanisms by which specific cell types adapt their replication process to their need to hyperproliferate - and how accelerated replication in early tumorigenesis contributes to genome instability and full transformation - is of crucial clinical relevance.

 

Goal

In this research line, we combine cell, molecular and structural biology methods to investigate the DNA replication process in specific cell types that constitutively hyper-proliferate or in tissues that are induced to hyper-proliferate in vivo under specific pathological conditions. The ultimate goal of our research is to uncover yet-elusive tissue-specific mechanisms of genome instability and tumorigenesis, linked to increased replication stress.

 

Ongoing and future work

We reported how mouse embryonic stem cells – both in culture and in their natural environment – experience a peculiar form of replication stress, linked to the rapid succession of genome duplication rounds and short intervening gap phases. These fascinating studies have been recently extended to haematopoietic stem cells, which are usually quiescent, but need to undergo hyper-proliferative bursts in response to specific stimuli, displaying unexpected adaptations of the DNA replication process. In collaboration with clinical labs in Switzerland and abroad, we are now interested in elucidating molecular mechanisms contributing to leukaemia development, which occurs when stem and progenitor cells acquire specific signs of genomic instability and undergo uncontrolled proliferation. Similarly, in collaboration with Achim Weber’s group at our Institute, we are investigating the liver as prototype of conditionally hyper-proliferating tissue. This tissue – which is typically quiescent in healthy adults - can regenerate by acute hyper-proliferation upon partial hepatectomy and undergoes compensatory hyper-proliferation under cancer-associated chronic liver disease. Combining mouse models and patient-derived organoids – in collaboration with the University Hospital Zurich – we are currently exploring the impact of replication stress on liver tumorigenesis and its possible exploitation for therapeutic purposes.

 

Selected publications

A. K. Ahuja, K. Jodkowska, F. Teloni, A. H. Bizard, R. Zellweger, R. Herrador, S. Ortega, I. D. Hickson, M. Altmeyer, J. Mendez and M. Lopes (2016). A short G1 phase imposes constitutive replication stress and fork remodeling in mouse embryonic stem cells. Nature Communications, 7:10660.

 

K. Jacobs, C. Doerdelmann, J. Krietsch, D. González-Acosta, N. Mathis, S. Kushinsky, E. Guarino, C. Gomez-Escolar, D. Martinez, J.A. Schmid, P. J. Leary, R. Freire, A. R. Ramiro, C. M. Eischen, J. Mendez and M. Lopes (2022). Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming. Molecular Cell, 82(21):4176-4188.e8. doi: 10.1016/j.molcel.2022.09.009

 

L.-A. Clerbaux, P. Cordier, N. Desboeufs, K. Unger, P. O. Leary, G. Semere, T. Y. Boege, L. K. Chan, C. Desdouets, M. Lopes and A. Weber (2023). Mcl-1 deficiency in murine livers leads to nuclear polyploidization and mitotic errors: implications for hepatocellular carcinoma. J. Hep Reports, accepted for publication