Humbert - Cancer biology, cell polarity and tissue architecture
Cell polarity, or asymmetry, is a fundamental property of all cells and is encoded by an evolutionarily conserved genetic program that coordinates the differential division of stem cells, the positioning of cells within an organ and ultimately the precise architecture of the organ. Disruption of this genetic program leads to the disorganization of tissue and can promote the first steps of cancer. Our laboratory is interested in how cell asymmetry and tissue organization can regulate cancer initiation, progression and metastasis with the ultimate aim to devise therapeutics to help tumours to “reorganize” themselves, thereby stopping the cancer’s growth and spread. In addition we are also interested in how the cell polarity genetic program may be involved in tissue regeneration as well as developmental processes such as blood cell production and function.
To drive this research, we have set up a multidisciplinary approach encompassing state of the art imaging, genetically-engineered mouse models and the use of powerful genetic and chemical screens. We work closely with cancer clinicians and pathologists.
“Re-organising” early breast and prostate cancer as a preventative approach
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.
The evolutionary origin of cancer
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.
The role of gravity in tissue organisation and regeneration
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.
How did the red blood cell lose its nucleus?
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.
Structural and biochemical characterisation of polarity complexes in development and disease
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
Meet the team
Fields of study
Cell development, proliferation and death; Cellular interactions; Cancer cell biology; Space Sciences; Breast cancer; Prostate Cancer; Cell Polarity; Erythropoiesis
Capabilities and techniques
3D cell cultures; Animal models of disease; Functional Screening; CRISPR-Cas9 gene editing; Microscopy - electron, confocal, light; Flow cytometry; Protein biochemistry; Microgravity Simulation; Real Microgravity experimentation, sounding rockets
Human patient-derived 3D organoid cultures; Pre-clinical animal models of cancer for drug screening.