Mechanisms of Paracrine and Endocrine Disorders (MoPED)
Team Leader
A. BARLIER
A. BARLIER
The MoPED team translates principles of developmental, molecular and stem cell biology into creative diagnostic and therapeutic approaches to solving the clinical problems arising at the interface of the nervous and endocrine systems. This branch of medicine is known as neuroendocrinology.
The neuroendocrine system includes vital endocrine glands such as the pituitary, thyroid and adrenal glands as well as endocrine islets within glandular or exocrine tissues (e.g. in the pancreas or elsewhere within organs derived from the embryonic endoderm). Neuroendocrine cells share a number of distinctive characteristics in common with neurons. Their hormone release requires signaling adjustments throughout life to maintain internal equilibrium of key functions in humans such as growth, reproduction, lactation, response to stress and metabolism.
Certain kinds of birth defects and tumors affect derivatives of the embryonic stem cell population known as the neural crest and are called congenital neurocristopathies. One of our team's lines of reseach explores the possibility that certain developmental or proliferative neuroendocrine diseases may also be "indirect" neurocristopathies.
Only 10% of patients with pituitary disorders have an identified genetic etiology. The treatment of neuroendocrine tumors (NET) remains highly challenging through their diversity, inaccessibility and incomplete knowledge of their etiology and pathophysiology. Understanding the exchanges and effects of paracrine and endocrine signals should provide creative solutions for the many patients affected with this wide array of often individually rare diseases.
The former DIP-NET team (Differentiation and Proliferation of Neuroendocrine Tissues) is grateful for the leadership of Pr. Thierry Brue, who remains an integral member of the MoPED team all while continuing to head the Endocrinology service at the Conception Hospital with Pr. Frédéric Castinetti. We are also pleased to integrate convergent themes from the research group of Dr. Heather Etchevers, who co-directs the MoPED team with Pr. Barlier since January 2024.
Please read on to learn more about our themes, specific projects, our networks and funders, and scientific production.
The developmental origins of this dispersed system are a little-known common thread underlying many specific pathologies and depend on coordinating signals exchanged between all “germ cell layers”. Cell proliferation and differentiation into hormone-secreting neuroendocrine phenotypes are tightly regulated by central and peripheral nervous system through other hormones, growth factors and cytokines and signal-bearing mesenchymal cells.
Instructions for what do to next are enforced by transcription factors in gene regulatory networks particularly important for the master endocrine organ, the pituitary. Defects in such regulation at any life stage, from embryogenesis to old age, leads to hormonal deficiencies or hypersecretion, which can induce opposing pathologies, like the canonical examples of dwarfism and gigantism.
A wide array of malformation syndromes arise from mutations also found in many adult cancers. Such mutations lead to constant activation of normally temporarily active enzymes in only some cell types and can be lethal, depending on when they occur. The result in survivors is inappropriate growth factor signaling, leading to effects on cell identities and tissue growth. The resulting organism is a mosaic of affected (mutated) and unaffected (non-mutated) cells. Their interactions during development can lead to diseases that appear very different from, but are mechanistically related to and sometimes predispose to, certain cancers.
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.
Mouse models used by our group phenocopy (reproduce many aspects of) syndromes found in human fetuses or children by directing the same types of mutations to distinct multipotent neural crest derivatives. This can affect not only their progeny in the skin but also in the heart, the peripheral nervous system, the pituitary or the skull. Characterizing these models and searching for equivalent mutations in relevant patient cohorts should lead to improved diagnoses and new therapeutic approaches for congenital neurocristopathies by repurposing drugs used in targeted chemotherapies.
A major experimental strategy underway is the design and validation of human organoid models from induced pluripotent stem cells (iPS) differentiated into neuroendocrine cell types of interest, such as specific pituitary cells.
To decipher signaling modules involved in therapeutic resistance in neuroendocrine tumors affecting pituitary function, we integrate proteomics data into mathematical models to prioritize signaling modules (in collaboration with the Baudot group). In parallel, we continue our drug screening strategy in collaboration with pharmacological companies Novartis and Inventiva on human primary cultures of tumors provided by neurosurgery and neuropathology departments of the AP-HM hospital network.
Please refer to the work conducted by Dr. Thi-Thom Mac during her doctoral thesis, under the supervision of Dr. Teddy Fauquier and Professor Thierry Brue, and published in eLife. The article is entitled: “Modeling of corticotropin deficiency using pituitary organoids confirms the functional role of NFKB2 in human pituitary differentiation.”
Using even more optimized protocols, the team continues to apply the differentiation of hormone-secreting organoids to study the effects of genes on pituitary dysfunction and tumor predisposition.
Dr. Pauline Romanet, MD PhD, has obtained a young researchers' starting grant (ANR JCJC) from the French National Research Agency in 2023, to develop an ambitious project called MEN1-PLUS on "New pathophysiological approaches to the study of multiple endocrine neoplasias type 1". We have recruited Dr. Giuliana Ascone to develop this project. She is leading an investigation into neural crest derivatives within the pituitary gland, using single-nucleus RNA-sequencing, and the role of MEN1 variants using pituitary organoids.
The large and giant congenital melanocytic nevus (CMN) is a visibly conspicuous malformation of the skin, present at birth. It can present as a restricted, stable and benign tumor, or be associated in syndromic form with additional cutaneous, neurological or oncological symptoms.
Dr. Daniel Aldea, senior post-doctoral scientist, is studying the effects of the molecular signaling pathways shown to be present in CMN in the embryological precursors to pigment cells using multiple systems and cutting edge -omics and imaging techniques:
Somatic mutations in NRAS and BRAF are the major molecular causes of CMN, and are also among the most prevalent drivers of malignant melanoma. Children born with rare and large forms of CMN have a dramatically increased chance of developing melanoma before the age of 30. Our lab is funded by the Horizon Europe program, MELCAYA (Novel health care strategies for melanoma in children, adolescents and young adults), to discover the molecular bases of the progression or intermediate stages between benign nevus and cancer in this emblematic neurocristopathy. We expect to apply the knowledge gained in other RASopathies, diseases due to undue activation of a large family of molecules in the cell that transduce paracrine and endocrine signals to the nucleus to change its behavior over time.
Prof. Barlier has been a pioneer in the study of these two types of intracranial tumors for many years. With industrial and clinical partners, as well as the expert application of Dr. Grégoire Mondielli, she is studying biochemical and signaling pathway modulation in these two broad entities in the anticipation of proposing novel therapies in preclinical and clinical trials to come.
This national consortium project, supported by a dedicated INSERM transversal program, launched just before the COVID-19 pandemic with the Zaffran group. It entailed mapping the specific transcriptomic signatures of each cell in the developing human heart in order to better understand normal and disease-associated physiology throughout life. A MMG collaboration led by Heather Etchevers, we participated in technology development with the GBiM platform and Baudot team and contributed unprecedently detailed data on the cellular composition, including rare neuroendocrine cells, of the first-trimester heart as it turns from a primordium into a functional and vital organ. This data is now part of the international Human Cell Atlas effort.
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