Current lab members:

• Dmitry Bulavin (PI), DR1 INSERM
• Laurent Grosse, IR CNRS
• Alexander Emelyanov, IR UCA
• Francisco Triana-Martinez, Postdoc INSERM
• Bogdan Grigorash, Postdoc INSERM
• Alessandra Pierantoni, PhD Student
• Ozmen Cobanoglu, Postdoc INSERM
• Alexia Boulois, IE CNRS, lab manager

Lab Alumni:

In our lab, we focus on a phenomenon known as cellular senescence, where cells cease to divide but do not die. Traditionally, these senescent cells are thought to contribute to the aging process and various age-related diseases. However, they also play beneficial roles, including in wound healing and cancer prevention.

We have developed unique genetic mouse models that allow us to trace and selectively eliminate cells marked by p16, a significant marker of senescence. Our research has revealed that the removal of these senescent cells can sometimes improve health outcomes, but it can also lead to unintended consequences such as liver and tissue fibrosis, ultimately deteriorating the organism’s healthspan.

Our findings underscore the complexity of senescence and caution against the indiscriminate removal of senescent cells as a strategy to combat aging. The work we do here emphasizes the need for nuanced approaches to manage senescence. We advocate for strategies that selectively target senescent cells, aiming to enhance health and longevity without causing adverse effects.

Our goal is to develop therapies that can mitigate aging and age-associat d disorders effectively and safely, enriching the quality of life. Join us as we continue to explore the fascinating and pivotal role of cellular senescence in life’s natural processes.

Current Projects

Recent Publications

• p16^High immune cell – controlled disease tolerance as a broad defense and healthspan extending strategy
  19 juillet 2024 par Francisco Triana-Martinez
  The ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens. Accumulating evidence, however, indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we report that p16^(High) immune cells play a key role in establishing disease tolerance. We found that the FDA-approved BNT162b2 mRNA COVID-19 vaccine is a potent and rapid inducer…
• p16^High senescence restricts cellular plasticity during somatic cell reprogramming
  31 août 2023 par Bogdan B Grigorash
  Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that removal of p16^(High) cells resulted in the 4FR of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the two-cell embryonic state, readily formed implantation-competent blastoids and, following…
• Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression
  14 décembre 2022 par Emmanuelle Born
  CONCLUSIONS: Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.
• LSEC model of aging
  15 juin 2020 par Laurent Grosse
  Data obtained from genetically modified mouse models suggest a detrimental role for p16^(High) senescent cells in physiological aging and age-related pathologies. Our recent analysis of aging mice revealed a continuous and noticeable accumulation of liver sinusoid endothelial cells (LSECs) expressing numerous senescence markers, including p16. At early stage, senescent LSECs show an enhanced ability to clear macromolecular waste and toxins including oxidized LDL (oxLDL). Later in life, however,…
• Defined p16^High Senescent Cell Types Are Indispensable for Mouse Healthspan
  3 juin 2020 par Laurent Grosse
  The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16^(Ink4a). Using a genetic lineage tracing approach, we found that age-induced p16^(High) senescence is a slow process that manifests around 10-12 months of age. The majority of p16^(High) cells were vascular…
• DNA Damage Signaling-Induced Cancer Cell Reprogramming as a Driver of Tumor Relapse
  8 avril 2019 par Doria Filipponi
  Accumulating evidence supports the role of the DNA damage response (DDR) in the negative regulation of tumorigenesis. Here, we found that DDR signaling poises a series of epigenetic events, resulting in activation of pro-tumorigenic genes but can go as far as reactivation of the pluripotency gene OCT4. Loss of DNA methylation appears to be a key initiating event in DDR-dependent OCT4 locus reactivation although full reactivation required the presence of a driving oncogene, such as Myc and…
• Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy
  9 octobre 2018 par Thomas Bertero
  Dysregulation of extracellular matrix (ECM) deposition and cellular metabolism promotes tumor aggressiveness by sustaining the activity of key growth, invasion, and survival pathways. Yet mechanisms by which biophysical properties of ECM relate to metabolic processes and tumor progression remain undefined. In both cancer cells and carcinoma-associated fibroblasts (CAFs), we found that ECM stiffening mechanoactivates glycolysis and glutamine metabolism and thus coordinates non-essential amino…
• Matrix Stiffening and EGFR Cooperate to Promote the Collective Invasion of Cancer Cells
  21 juillet 2018 par Eloise M Grasset
  In squamous cell carcinoma (SCC), tissue invasion by collectively invading cells requires physical forces applied by tumor cells on their surrounding extracellular matrix (ECM). Cancer-related ECM is composed of thick collagen bundles organized by carcinoma-associated fibroblasts (CAF) within the tumor stroma. Here, we show that SCC cell collective invasion is driven by the matrix-dependent mechano-sensitization of EGF signaling in cancer cells. Calcium (Ca^(2+)) was a potent intracellular…
• Cancer suppression by systemic inactivation of p38MAPK
  16 février 2017 par Anna Brichkina
  No abstract
• p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis
  24 décembre 2016 par Anna Brichkina
  Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer…
• Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions
  28 mai 2016 par A Brichkina
  The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In…
• Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)
  23 janvier 2016 par Daniel J Klionsky
  No abstract
• Wip1 phosphatase in breast cancer
  11 novembre 2014 par A Emelyanov
  Understanding the factors contributing to tumor initiation, progression and evolution is of paramount significance. Among them, wild-type p53-induced phosphatase 1 (Wip1) is emerging as an important oncogene by virtue of its negative control on several key tumor suppressor pathways. Originally discovered as a p53-regulated gene, Wip1 has been subsequently found amplified and more recently mutated in a significant fraction of human cancers including breast tumors. Recent development in the field…
• Oncogene-mediated regulation of p53 ISGylation and functions
  30 juillet 2014 par Yi-Fu Huang
  Oncogene-mediated cellular transformation is a multistep process involving activation of growth-promoting pathways as well as inactivation of tumor suppressors. We recently found that ISGylation of the p53 tumor suppressor is an important novel mechanism to control its stability. Here we identified that Isg15-dependent regulation of p53 can be enhanced by different oncogenes. We further show that the Src-mediated phosphorylation of p53 on Tyr126 and Tyr220 has a positive effect on p53 ISGylation…
• Isg15 controls p53 stability and functions
  22 mai 2014 par Yi-Fu Huang
  Degradation of p53 is a cornerstone in the control of its functions as a tumor suppressor. This process is attributed to ubiquitin-dependent modification of p53. In addition to polyubiquitination, we found that p53 is targeted for degradation through ISGylation. Isg15, a ubiquitin-like protein, covalently modifies p53 at 2 sites in the N and C terminus, and ISGylated p53 can be degraded by the 20S proteasome. ISGylation primarily targets a misfolded, dominant-negative p53, and Isg15 deletion in…

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