Master2 Internship offer on Metabolic regulations by the tumor suppressor kinase LKB1 during neural
crest development: nuclear function and crosstalk with p53, at Institute for Advanced Biosciences – Grenoble, from January to June 2020.
The tumor suppressor LKB1 is a master kinase controlling many cell processes through the
activation of several downstream kinases including in particular the energy sensor AMPK. In an attempt
to better understand how LKB1 coordinately regulates cell polarity and metabolism, we recently uncover
LKB1 as a new metabolic regulator of stem cell fate especially during glial differentiation, through the
tuning of non-essential amino acid levels and subsequently the mTOR pathway.
We generated several models of spatio-temporal inactivation of Lkb1 in polarized cells such as
neural crest cells (NCC). These embryonic stem cells originate from the neural tube and give rise to a
broad range of derivatives such as the melanocytes and the neurons and glial cells of the peripheral
nervous system (the peripheral nerves and the enteric nervous system). Mice with early Lkb1
inactivation in NCC died at birth due to craniofacial malformations (Creuzet et al., 2016, Dev Biol
418:283-296). Mice with late ablation of Lkb1 in NCC exhibited a hypopigmented coat, an intestinal
pseudo-obstruction and a peripheral neuropathy. Together, the complex phenotypes triggered by Lkb1
loss in NCC are reminiscent of human pathologies due to defects in NCC development so-called
By using neural crest stem cells that can be differentiated to glial cells in vitro, we identified that Lkb1
silencing impaired glial differentiation in association with increased alanine and glutamate
concentrations and upregulation of the mTOR pathway. Our results uncovered that normalizing the
amino acid levels was sufficient to rescue glial differentiation in vitro and to prevent the neurocristopathy
in vivo (Radu et al., 2019, Sci Advances 5:eaau5106; PMID 31328154; Radu et al., In preparation).
More recently, we identified that during glial differentiation, Lkb1 knockdown triggers
hyperphosphorylation and activation of the tumor suppressor p53, another major metabolic regulator.
Ablation of p53 both in vitro and in vivo was able to rescue at least partially NCC-derived glial
differentiation and the neurocristopathy phenotype. LKB1 shuttles between the nucleus and the
cytoplasm but its putative nuclear function remains poorly studied. We observed that LKB1 and p53
interact together both in the cytoplasm and the nucleus. However, their associations both in the nucleus
and cytoplasm are so far underexplored.
A better understanding of how p53 is activated upon LKB1 loss
and how p53 activation impacts the metabolic status of LKB1 null cells
is thus crucial. Based on our preliminary data, we hypothesize that
LKB1 could have a new nuclear function to coordinately regulate cell
metabolism and fate partly though p53. In collaboration with PhD
students in the team, the M2 student will thus further explore LKB1-p53
balance in NCC and if LKB1 nuclear function is required to modulate
cell metabolism and fate. In the lab, we are also exploring how these
regulations exerted by LKB1 are essential for its tumor suppressor
activity studying lung cancer model.
Supervisor: Chantal Thibert, CR1, CNRS, 04 76 54 95 75
Contact e-mail: email@example.com
Team leader: Pierre Hainaut, PUPH
Institute for Advanced Biosciences
Site Santé Allée des Alpes
38700 La Tronche Cédex
Team Website: https://iab.univ-grenoble-alpes.fr
Languages spoken in the lab: French/English
Date: January-June 2020