Research
Tumor microenvironnement and resistance to treatment : A. Turtoi

Despite advances in cancer research, surgery remains the primary treatment for localized tumors. Metastasis is the leading cause of cancer-related deaths, and no current therapy prevents its occurrence. Tumors' ability to adapt and resist to treatments, driven by intratumoral heterogeneity, contributes to chemotherapy failure. Additionally, tumors rely on the tumor microenvironment (TME)—a network of fibroblasts, endothelial cells, neurons, and immune cells—for growth and resistance to therapy. Among these, cancer-associated fibroblasts (CAFs) are key sources of growth factors, energy substrates, extracellular matrix proteins, and immune molecules. Our lab focuses on primary (hepatocellular) and secondary liver cancers (metastases from pancreatic and colon cancers). We study the molecular interactions between cancer and stromal cells, specifically CAFs that support tumor growth. Our research aims to identify new cancer biomarkers for diagnosis and therapy, and develop innovative antibody-based therapies to target cancer and combat cancer-related conditions like cachexia.

Axis 1:  Identification of CAF subpopulations involved in tumorigenesis

Although targeting CAFs is a promising therapeutic approach, the heterogeneity of cancer stromal cells remains poorly studied. Our aim is to characterize the different subpopulations of CAFs and determine their function in tumorigenesis (Fig 1). Then, we identified defensive CAFs with antitumor properties in breast cancer¹ and hepatocellular carcinoma¹. We have also described different CAFs subtypes in liver metastasis from colon cancer by using single cell analysis and RNAseq². Finally, we used spatial transcriptomic to map CAFs heterogeneity in human breast cancer (n=75)³ (Collab. Gumma University, Japan). Our present efforts focus on cancer cells-CAFs interactions able to antagonize tumor growth through metabolite-receptor communication systems.

 Axis 2: Function and targeting of soluble factors in cachexia in colorectal cancer  

One-third of cancer patients die from a weight loss caused by cachexia. Due to tumor-induced metabolic reprogramming, muscle and fat cells degrade their contents for energy. High levels of inflammatory cytokines in cachexia patients lead to a combination of systemic organ damage, such as muscle atrophy, decreased appetite and metabolic disorders. Our team is focused on TGF-β, a key player in aberrant inflammation both in cancer and cachexia. We aim to better understand TGF-β's function and its targets, especially its role in muscle degradation through autophagy, among other. Thanks to our expertise in antibody engineering⁴ (patent WO2020104496 and Labex MabImprove), TGF-β will be specifically targeted with of aim of decreasing cachexia.

Axis 3: Cancer biomarkers: Detection of soluble biomarkers of pancreatic ductal adenocarcinoma (PDAC) with endoscopic ultrasound-guided fine-needle aspiration samples (EUS-FNA)

Due to late diagnosis, PDAC prognosis is poor. To improve PDAC management, diagnostic biomarkers are urgently needed.  While EUS-FNA is the cornerstone of PDAC diagnosis, this invasive procedure is reserved to patients suspected of having PDAC. We recently developed a non-destructive OMICS-compliant method to extract soluble molecules from EUS-FNA (collab Pr. Eric Assenat, CHU Montpellier). In a retrospective study of 58 patients with suspected of having PDAC, proteins from the fluid of EUS-FNA were analyzed by mass spectrometry. Proteomic and clinical data were used to identify a protein signature useful for PDAC diagnosis⁵ (collab. Pr. Jacques Colinge) (PANEXPEL clinical trial: NCT03791073). For improvement and further validation, PanEXPEL2 cohort (NCT04370574, Montpellier and Toulouse University Hospital) is recruiting.