Macrophages do not only play a beneficial role in our immunity. Indeed, the massive tissue infiltration of macrophages derived from blood monocytes has a deleterious effect in most cancers and chronic inflammations, among other pathologies. It is therefore important to dissect the molecular mechanisms involved in the deleterious infiltration of tumor-associated macrophages in order to modulate it. In dense tumors, macrophages use the mesenchymal mode of migration, which requires proteolysis of the extracellular matrix, and the formation of adhesion structures called podosomes.

The proposed project is part of an interdisciplinary research program that combines cutting-edge and innovative techniques in optical and electron imaging, cell mechanics and materials science. It will build on our complementary expertise in podosome mechanobiology and cryo-electron tomography in situ to decipher the influence of nanoscale substrate topography on macrophage podosomes, the molecular mechanism involved in macrophage topography sensing and its importance for the infiltration of tumor-associated macrophages.

DNA double-strand breaks (DSBs) are toxic lesions, holding the potential to generate mutations and translocations. DSBs were historically seen as rare, mostly therapy-induced DNA lesions. However, recent work unequivocally revealed that endogenous DSBs occur far more frequently that initially believed, including in physiological conditions such as neuron stimulation, and mainly fall within transcribed loci (Transcription Coupled DSB, TC-DSB). Notably, altered repair of TC-DSBs is not only emerging as a driver of oncogenesis but also of many developmental, neurological and aging-associated diseases.

Using high throughput genomic and an original dedicated cell system (the DIvA cell line) our lab pioneered the discovery of a dedicated pathway mobilized to repair such DSBs in transcribed loci, coined as Transcription Coupled DSB repair (TC-DSBR). Grounding on our previous work, the present project aims at investigating TC-DSBR in stimulated neurons where endogenous TC-DSBs are generated as a consequence of early responsive genes activation.

Holding a strong background in bioinformatics the PhD student will:

1. Analyze and integrate the vast amount of high-throughput genomics data already obtained in DIvA cells (ATAC-seq, RNA-seq, ChIP-seq and HiC) to get a comprehensive view on the chromatin restructuration induced by TC-DSBs, to stage up the stage for the second aim.
2. Investigate using stimulated primary mouse neurons and human minibrains the repair processes at work at these endogenous TC-DSBs, using bulk and single cell Cut&Tag approaches. Sc Cut&Tag will be performed in Jop Kind’s lab (Hubrecht institute) who is a leader in the development of single cell genomics approaches.

The use of digital biomarkers for early detection of functional or cognitive decline is receiving increasing attention. For example, sensor-derived mobility indicators have been studied to predict an upcoming fall in the elderly. Currently, assessment of an individual’s food intake behavior relies primarily on self-report measures with a major recall bias. Continuous real-time sensor monitoring may provide a more sensitive and environmentally valid method. It is well demonstrated that the detection of subclinical alteration of nutritional habits (e.g. meal time, frequency, meal preparation…) combined with physiological parameters (weight, body composition, mobility) can prevent disease or social isolation.

In this work, we propose to develop digital biomarkers to track nutrition-related outcomes. We hypothesize that changes in meal intake or meal preparation outcomes correlated to physiological health characteristics (e.g. weight) could give predictive signs of deterioration but also that the monitoring of these parameters could give useful information on the dynamics of recovery after a hospitalization or a surgery for example. The proposed system is composed of a set of low cost sensors and embedded algorithms installed in the home to detect subtle changes on different time scales (weekly to yearly).

Finally, the development of digital biomarkers should allow better specification of the innovative services to be implemented to ensure their scalability and integration into the care pathway. This project associating a technological research center and a clinical center of excellence will benefit from the observational cohort of 100 elderly people continuously monitored with sensors at home for 5 years (INSPIRE-T project).