Humbert - Cancer biology, cell polarity and tissue architecture

Loss of the proper orientation of cells within a tissue, known as cell polarity, is one of the hallmarks of breast and prostate cancer and is correlated with more aggressive and invasive cancers. How loss of cell polarity occurs and how it contributes at the molecular level to tumour formation remains unknown. Using several approaches including RNAi screening, our laboratory has identified a network of genes that mediate the tumour suppressive functions of cell polarity. We are using this new molecular information to re-establish normal tissue architecture through clinically approved drugs, with the aim to stop early tumour growth in a preventative setting.

How did cancer begin? The advent of the first multicellular animals from single cells required new molecular mechanisms that allowed cooperation between cells and suppressed any conflicts that enhanced the individual fitness of any one cell, stopping them from “cheating” to the detriment of the organism. We are investigating these very first cancer protective mechanisms in one of the oldest and simplest animals on earth known as Trichoplax.(Figure 1). Despite 65 million years of evolution, the majority of human disease genes including cancer suppressing genes can be found in Trichoplax. By understanding, how this ancient organism escapes cancer, we hope to gain fundamental insights into the origins of cancer that will be translated to humans.

Since the dawn of life on Earth, some four billions of years ago, gravity has been the only constant environmental factor that accompanied the evolution of life. It is unknown, however, what role gravity has been playing with respect to the establishment and maintenance of the tissue organisation of multicellular organisms. A variety of physiological effects resulting from hypergravity or microgravity (weightlessness) have been noted with detrimental effects on bone and muscle turnover, and wound healing in humans. This is a crucial factor in the context of international space programs which aim at a long-term stay of humans and bioregenerative life support systems in space.

Through our close connection with the German Aerospace Center (DLR), and in partnership with TiHo, Hannover, we are testing for the first time how altered gravity may affect the development of tissue architecture and regenerative programs in the simplest and most ancient animal, Trichoplax.  We are utilising short-term space flights in sounding rockets and ground-based microgravity simulators to provide new insights into how all animal tissues are organised and regenerated.

Red blood cell enucleation (extrusion of the nucleus) is a defining feature of mammalian blood that is required for proper circulation of red blood cells (RBCs) through the microvasculature and increased haemoglobin concentration in the blood. With a large proportion of surgical and cancer patients undergoing blood transfusions as part of their treatment, a major challenge for transfusion medicine is the constant difficulties in obtaining sufficient supplies of specific RBC subtypes.

Despite exciting advances in the in vitro production of human red blood cells from hematopoietic, embryonic, and induced pluripotent stem cells, the reduced ability of these cultured cells to fully enucleate remains a major hurdle. We are investigating the molecular mechanisms regulating the enucleation process to provide improved strategies for the efficient and rapid production of RBCs for autologous (self-generated) patient transfusion.

Every cell in our body has an intrinsic orientation (or polarity) that is controlled by a universal set of genes known as polarity genes. Loss of this orientation is a defining early feature in cancers, and has been linked to cancer spread or metastasis. Our team has previously identified the gene Scribble as a new human polarity gene that controls cell orientation and whose deregulation increases the risk of cancer by disorganizing the tissue and by increasing the speed at which cells grow within the tissue. In addition, mutation in Scribble and associated genes can lead to life-threatening birth abnormalities such as spina bifida.

This project will establish how Scribble and its biochemical partners contribute to developmental defects and tumour formation by clarifying their molecular mechanism of action and thus enable targeting of these proteins for therapeutic purposes. To achieve this, we biochemically characterize the interactions between Scribble and known and novel biochemical partners using a variety of biochemical, high-resolution imaging techniques and functional assays. Using X-ray crystallography and Cryo-electron microscopy (Cryo-EM), it can be shown in atomic detail how they perform their function. Gaining deeper insight into the nature of the interactions that allow Scribble and its partners to perform its function will be critical to formulate novel anti-cancer compounds that aim to exploit the loss of polarity in cancer cells. All structural and biochemical information will be validated for their functional relevance in our well established mouse and cellular models, and therefore rapidly translated into biological information directly relevant to human cancer patients and their outcome.

In collaboration at with Professor Marc Kvansakul LIMS

Group leader

Professor Patrick Humbert

PhD students

Samantha Melrose