Description of the PhD thesis project
While tumors include very heterogeneous
neighbour cells, early embryonic tissues are often patterned in a graded manner
with fields of similar cells. However, recent single cell (SC) transcriptomics
uncover micro-heterogeneities in otherwise similar cells, which could prefigure
patterning transitions or cell behaviors such as epithelial-mesenchymal
transition (EMT) and cell migration. It remains unknown if cells differing only
by few specific gene expressions are neighbors forming a mosaic tissue or
organized in homogeneous groups spatially.
This question especially applies to
transitional tissues such as the neural crest or metastases and is critical to
understand development or the aberrant reactivation of embryonic programs in
cancer. Spatial transcriptomics is a key emerging approach revealing combined
gene expressions in single cells in their in vivo environment. We focus on the
control of neural crest patterning, EMT and cell migration in embryos and on
metastasis in cancer. Our SC analyses point at specific gene co-expressions at
the individual cell level to control these processes.
This Ph.D. project will establish a temporal
single cell map of gene co-expression in these processes, using SC
transcriptomes, spatial SC imaging, and crispr-cas9-guided genetic
perturbations both in xenopus embryos and a zebrafish model of metastasis. It
will be conducted at Institut Curie with secondments and co-supervision of
academic (USA) and industrial (France) supervisors.
Objectives
This Ph.D. project is fully integrated in the
team's larger project and benefits from preliminary data and well-established
approaches mastered by the team or the collaborators. This project will focus
specifically on a key patterning event defined from our recent single cell (SC)
analyses, identifying an important cell state transition in cranial neural
crest cells, and potentially driving their highly invasive character (they
massively populate long-distance tissues forming our vertebrate head). This
program involves several neural crest derivatives (pigment, neurons, bone...),
and the interplay between fate choices and migratory behaviors will be
explored.
The first objective will establish the spatial
molecular map of gene co-expressions at SC level, by integrating a highly
structured team steered by our group (funded ANR project), which establishes
spatial transcriptomics to detect multiple gene co-expressions during early
development. This map will reveal the spatial organization of the cells
undergoing fate and behavior decisions, driving hypotheses for experimental
perturbations in vivo.
Second objective will use experimental
embryology tools to understand the logic of these regulations in the controlled
context of embryonic EMT.
Third objective will use human melanoma cell
lines well characterized in the team to evaluate if the identified gene
co-expressions are reactivated in those cells and if they are involved in the
cell’s invasiveness in vivo.
International, interdisciplinary &
intersectoral aspects of the project
International
International co-supervision by Prof. Leon
Peshkin, Harvard Medical School, Systems Biology Department, with whom we have
a long-standing collaboration (article on single cell transcriptomics in
developing neural crest currently in revision, second article being written).
The PhD student will visit for one-month secondment and do analysis of SC data.
Intersectoral
Collaboration and secondment at industrial
(SME) partner (Azelead, Montpellier, France) who has a patented model of in
vivo metastasis for melanoma cells in zebrafish. We have an on-going
collaboration with them (ITN network that I coordinate) and two current
collaborations with current PhD students in the lab. PhD candidate will do 2
one-month secondments in the industrial partner
Interdisciplinary
Ph. D. Student will receive training in
bioinformatics and statistics to be able to understand, use and modify the
team’s custom-made pipelines for single cell transcriptome analysis; will also
receive training in advanced imaging, in vivo (spatial transcriptomics and cell
migration). PhD student in parallel will be trained in biology (in vivo and in
vitro cell and developmental biology).
Recent publications
- Alkobtawi
M, Pla P, Monsoro-Burq AH*. BMP
signaling is enhanced intracellularly by FHL3 controlling WNT-dependent
spatiotemporal emergence of the neural crest. Cell Rep. 2021 Jun 22;35(12):109289. doi: 10.1016/j.celrep.2021.109289. PMID: 34161771.
- Kristin
B Artinger*, Anne H Monsoro-Burq*. Neural crest multipotency and specification:
power and limits of single cell transcriptomic approaches. Faculty Reviews 2021
10:(38) (14 Apr 2021). https://doi.org/10.12703/r/10-38
- Scerbo P and Monsoro-Burq A.H.* (2020) The
vertebrate-specific VENTX/NANOG gene empowers neural crest with ectomesenchyme
potential, Science Advances 29 Apr 2020: Vol. 6, no. 18, eaaz1469 DOI: 10.1126/sciadv.aaz1469, PMID: 32494672
- Plouhinec JL, Medina-Ruiz S,
Borday C, Bernard E, Vert JP, Eisen MB, Harland RM, Monsoro-Burq AH*. A
molecular atlas of the developing ectoderm defines neural, neural crest,
placode, and nonneural progenitor identity in vertebrates. PLoS Biol. 2017 Oct 19;15(10):e2004045. doi: 10.1371/journal.pbio.2004045.
eCollection 2017 Oct. PubMed PMID: 29049289; PubMed Central PMCID: PMC5663519.
- Figueiredo
AL, Maczkowiak F, Borday C, Pla P, Sittewelle M, Pegoraro C, Monsoro-Burq AH*. PFKFB4
control of AKT signaling is essential for premigratory and migratory neural
crest formation. Development. 2017 Nov 15; 144(22):4183-4194. doi:
10.1242/dev.157644. Epub 2017 Oct 16. PubMed PMID: 29038306.