The branch of medicine concerned with the interactions between nervous and endocrine systems is called neuroendocrinology. These act together to regulate many physiologic processes of the human body. The neuroendocrine system includes endocrine glands such as the pituitary and adrenal glands as well as endocrine islets within glandular tissues (e.g. pancreatic tissue) and cells dispersed between exocrine cells, such as endocrine cells of the digestive tract.
All neuroendocrine cells share a number of distinctive neuronal characteristics, such as dense core secretion granules containing peptides, biogenic amines and some antigens in common with nerves. Hormone release from neuroendocrine cells is a highly regulated process that requires adjustments to maintain internal equilibrium throughout life of key functions in humans such as growth, reproduction, lactation, response to stress and metabolism.
Cell proliferation and differentiation into hormone-secreting neuroendocrine phenotypes are tightly regulated by hypothalamic factors, hormones, growth factors, transcription factors etc. Defects in such regulation at any life stage, from embryogenesis to old age, leads to hormonal deficiencies or hypersecretion inducing opposing pathologies, like the canonical examples of dwarfism and gigantism.
DIP-NET (Differentiation and Proliferation of Neuroendocrine Tissues) was created in 2017 by the merger of two former research teams of the now-defunct CRN2M (CNRS UMR 7286) with a shared interest in neuroendocrinology. Prof. Thierry Brue's group studied the “role of transcription factors in pituitary pathophysiology,” and Prof. Anne Barlier's group focused on “signaling in neuroendocrine tumours”. These teams had also been working for a number of years in collaboration within the AP-HM hospital system through Prof. Brue's coordination of the nationally accredited Reference Center for Rare Pituitary Diseases "DEFHY", now HYPO. In 2021, with convergent interests in basic pathophysiological mechanisms, they were joined by Dr. Heather Etchevers and her group in the MMG department. Together, they are exploring the effects of changes in shared signaling and transcriptional pathways mediating communication both within and between the diverse cell types of neuroendocrine organs, particularly the pituitary gland.
Our main objectives are to identify and understand the roles of key elements (from receptors to transcription factors) involved in the mechanisms of differentiation and proliferation of neuroendocrine cells. Elucidating the physiological influences of molecular pathways and their abnormalities that can cause hormone deficiencies, neuroendocrine hypersecretion or proliferative syndromes are helping our team develop new therapeutic strategies for these disorders.
To increase the rate of identification of genetic causes, we have developed high-throughput genomic analyses, from gene panels using high-throughput sequencing to comparative hybridization (CGH) and whole-exome studies. These strategies are used for both pituitary deficiencies (the international GenHypoPit network) and hereditary NETs (TENGEN network), in collaboration with the AP-HM Molecular Biology Laboratory, directed by Prof. Barlier.
These large-scale genomic technologies are allowing us to identify new genomic abnormalities. However, pathologies of the neuroendocrine system are rare diseases and relevant cellular models are lacking. Human cells are poorly accessible while murine models display a number of discrepancies with human neuroendocrine physiology and pathology. In specific contexts, they are used in our group to trace and study specific effects of signaling pathway activation on neuroendocrine differentiation and proliferation in vivo. However, a major experimental strategy underway is the validation of human organoid models from induced pluripotent stem cells(iPS) differentiated into neuroendocrine cell types of interest, such as specific pituitary cells.
Endocrinology is a field of medicine where therapies can be provided by hormonal replacement or inhibitors of their secretion. However, current hormonal therapies poorly mimic physiological secretion in general, resulting in altered quality of life. To progress in the treatment of NET (neuroendocrine tumors), we conducthigh-throughput proteomics analysesto decipher signaling modules involved in therapeutic resistance. These proteomic data are integrated into mathematical models to identify important signalling modules for NET biology (in collaboration with the group of Dr. A. Baudot). In parallel, we continue our drug screening strategy in collaboration with pharmacological companies on human primary cultures of tumors provided by neurosurgery (Prof. H. Dufour) and neuropathology (Prof. D. Figarella-Branger) departments of the AP-HM.
We have thus established favorable conditions to delineate molecular mechanisms leading to human pituitary deficiencies and tumors and to test new therapeutic strategies for such diseases. The availability of a unique collection of genomic DNA samples and neuroendocrine tumors with well characterized phenotypes, our genomic databases, clinical expertise in pituitary diseases and their treatments, newly reinforced expertise in experimental developmental biology and our longstanding national and international collaborations in the field of rare diseases are major strengths of our projects.