Contribution of Tumor RHeology in Resistance to

**Contribution of tumor rheology in resistance to immunotherapies of non-small cell lung cancers**:

- Réf **ABG-127312**
- Sujet de Thèse- 02/12/2024- Contrat doctoral- Dynamics and nanoenvironment of biological membrane- Lieu de travail- Marseille - Provence-Alpes-Côte d'Azur - France- Intitulé du sujet- Contribution of tumor rheology in resistance to immunotherapies of non-small cell lung cancers- Champs scientifiques- Santé, médecine humaine, vétérinaire
- Biologie
- Physique
- Mots clés- Tumeur poumon, microscopie a force atomique, Rhéologie**Description du sujet**:
Lung tumors incidence is steadily increasing especially, non-small cell lung cancer (NSCLC) subtypes. According to the WHO, it is the leading cause of cancer mortality worldwide, accounting for nearly 1.8 million deaths. In France, 53.000 new cases have been recorded in 2022, and with a five-year survival rate of less than 20%, lung cancer is a real public health issue. Recently, the range of treatments has expanded with the development of immunotherapies. Restricted in lung to date to immune-checked point inhibitors (ICI) which target the PD-1/PDL1 pathway by antagonistic antibodies. The marked improvement in the management of this pathology by these therapies has tended to make it a first-line treatment, either in a curative approach or as a neoadjuvant treatment when resection is possible. However, although these approaches have led to substantial progress, the efficiency of these treatments remains heterogeneous, and resistance and relapse are common. Defining the mechanisms responsible for or contributing to such resistance is a major challenge in oncology. Mechanical contribution has not been investigated yet whereas lungs are intrinsically a tissue in which mechanical stress is of obvious importance related to respiration motions. Determining whether the mechanical properties of tumor cells and their microenvironment play a role in NSCLC resistance to ICI immunotherapies and potential relapse is the core and the main objective of this thesis project. To this end, we propose to exploit and analyze patient samples referenced, available, stored and provided by the Biological Resources Center (CRB) of the AP-HM. These samples from patients treated with ICI in a neoadjuvant context prior to resection will be used to generate rheology maps (stiffness and viscoelasticity) by atomic force microscopy (AFM) and correlate them with immunolabeling characterizing the immune infiltrate. The superposition of these different maps will then be performed and analyzed to correlate mechanical properties with the nature, abundance and location of the immune infiltrate. The analyses will be performed by a bioinformatician in collaboration with a theoretical modeler. To maximize the translational aspect of the project and to be closest to the health care needs, we will focus on NSCLC subtypes for which no efficient treatments are available, and ICI are prescribed by lack of alternative options even if they are considered like inefficient. Among these problematic subtypes those harboring oncogenic expression of KRAS associated with the inactivation of STK11 or KEAP1 genes have been chosen. At completion this translational and interdisciplinary thesis would determine the tumor mechanical contribution to ICI resistance, define a model of immune infiltrate according to tumor rheologic features and better characterize two NSCLC subtypes without therapeutical answer. Coordinated by Dr. Michael Sebbagh biologist at DyNaMo research unite UMR1325, it will also involve AP-HM lung oncologists. The study will be carried out within the Inserm Interdisciplinary unit DyNaMo which has all the equipment and expertise required for the project to run smoothly.

**Prise de fonction**:

- 03/03/2025**Nature du financement**:

- Contrat doctoral**Précisions sur le financement**:

- La demande prête à être soumise. Résultat en Janvier Février **Présentation établissement et labo d'accueil**:

- Dynamics and nanoenvironment of biological membraneDyNaMo est une unité de recherche INSERM sur le campus de l'Université Aix-Marseille de Luminy.

Cette unité interdiscplinaire regroupe Physicient, Biologiest, Neurologiste et Theoricient afin de mieux comprendre le vivant par des approches multiples et complémentaires.

**Site web**:
**Intitulé du doctorat**:

- Doctoral de Biologie / Biophysique**Pays d'obtention du doctorat**:

- France**Etablissement délivrant le doctorat**:

- Aix-Marseille Université**Ecole doctorale**:

- Sciences de la vie et de la santé**Thèse en cotutelle **:Oui
- **Pays d'obtention du doctorat en cotutelle**:

- France**Etablissement délivrant le doctorat en cotutelle**:

- Aix-Marseille universitéLe projet est centré sur des mesures et microscopie atomique et photonique suivie d'une analyse d'image correlative. Une expertise dans ces disciplines et en traitement et analyse d'image est un plus.

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