BARLIER Anne / ETCHEVERS Heather

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 GEnOPé, directed by Prof. Barlier.

A major experimental strategy underway is the design and validation of human organoid models from induced pluripotent stem cells (iPS) differentiated into cell types of interest, such as neuroendocrine or neural crest-derived cells.

In collaboration with pharmacological companies Novartis and Inventiva, we benchmark potential new therapeutic compounds on human primary cultures of tumors provided by neurosurgery and neuropathology departments of the AP-HM hospital network.

We use single-cell and spatial transcriptomics and DNA methylomics on human and animal samples, as well as microscopy and lineage-tracing in conditional murine models to better understand pathophysiological mechanisms

Dr. Thi-Thom Mac, alumna under the supervision of Dr. Teddy Fauquier and Professors Frédéric Castinetti and Thierry Brue, optimized an important 3D model of directed differentiation of human stem cells.

With further optimized protocols by multiple team members, we continue to perfect hormone-secreting organoids to study the effects of genes on pituitary dysfunction and tumor predisposition.

Dr. Pauline Romanet, MD PhD, 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.

Pauline obtained a prestigious INSERM "contrat d'interface" fellowship to spend even more time in the research lab from 2026-2031, and was featured on the citywide (AP-HM) hospital webpage.

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:

• Surgical and pathology specimens from large and giant congenital melanocytic nevi (CMN)
• Induced pluripotent stem cells from human CMN
• Comparative transcriptomics in primary cultures of mouse cells from neural crest-specific induction of constitutively active BRAF or NRAS mutations
• Phenotypic characterization of mouse models with different onset or compartments of BRAF or NRAS mutations during prenatal and postnatal development, in order to understand cell non-autonomous effects in CMN syndrome and related disorders

Daniel will pursue his career as staff scientist at the prestigious OIST in Okinawa, Japan, on the topic of evolutionary genomics of the skin as of 2027.

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 was funded by the Horizon Europe program, MELCAYA (Novel health care strategies for melanoma in children, adolescents and young adults), through the end of 2026 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.