The Centre de Recherche en Cancérologie de Marseille (CRCM) pursues its mission of excellence through nationally and internationally recognized research.

Here you’ll find the scientific publications of recent weeks, the fruit of the work of the center’s teams. They illustrate the richness and diversity of the themes explored in the fight against cancer, from fundamental to translational research.

Headlines

BTN2A1 acquisition through trogocytosis enhances Vγ9Vδ2 T cell cytotoxicity against autologous and cancer cells.

OHIO Department, Nunès / Devillier team

Butyrophilins (BTNs), are molecules involved in the activation of specific cytotoxic T lymphocytes possessing a T cell receptor (TCR) expressing γ and δ chains (LT γδ) in place of the α and β chains of the more conventional ^CD4+ and ^CD8+ T lymphocyte TCRs. BTNs are expressed at the cell membrane, almost ubiquitously for BTN2A1, and after overexpression mediated by cellular activation or inflammation for BTN3A. These two molecules function as heterodimers, enabling the activation of γδ LTs. Recently, these molecules have been studied as novel immune checkpoint (IC) markers, leading to the development of drugs currently in clinical trials (ICT01, Imcheck Therapeutics). However, the regulation of the expression and function of these molecules remains poorly understood.

In our paper, we demonstrated that BTN2A1 expression increases with TCR stimulation, via anti-CD3/CD28 antibodies, and that this increase is mediated by trogocytosis function in the presence of activated myeloid cells (e.g. monocytes). Trogocytosis characterizes the exchange of cell membrane parts or fragments and associated cytosol. This occurs during cell contacts, which may be due to activation or a pathological process. During trogocytosis, the molecules present on the transferred membrane fragment are preserved.

We have shown that BTN2A1 can be acquired by trogocytosis by BTN2A1-depleted B lymphocytes (BTN2A1-KO) in cocultures with activated monocytes, which express it naturally. We hypothesized that a gain of BTN2A1 at the cell membrane via trogocytosis might induce enhanced sensitivity to LT γδ, and this is what we demonstrated. Indeed, normal or tumor cells that had acquired BTN2A1 via trogocytosis were more sensitive to lysis by LT γδ when we measured cell death by Caspase 3 and 7 production. Finally, we demonstrated BTN2A1 acquisition by circulating lymphocytes, via monocyte activation, in a cohort of 87 endometrial cancer patients.

Our study has revealed a new aspect of the regulation of BTN2A1 expression and functions, as well as the importance of trogocytosis in the regulation of CI expression in pathophysiology. Indeed, trogocytosis is a mechanism which, under physiological conditions, could participate in the elimination of autoreactive lymphocytes by γδ LTs. In pathology, and particularly in oncology, this acquisition of BTN2A1 could induce better tumor elimination after treatment. It is also becoming important to consider the effect of trogocytosis in supervised analyses, where there is a tendency to exclude markers that “don’t belong” to a cell type or are considered aberrant.

And also…

OHIO Department

Nunès / Devillier team

Vγ9Vδ2 T Cells Express an Antitumor Profile Associated with Anti-PD-(L)1 Responses and Activation Defects Restored by Anti-BTN3A in Triple-Negative Breast Cancer. Improving transparency and empowerment for cancer patients by accessing their full online personal medical records. Tremelimumab plus durvalumab combined to metronomic oral vinorelbine: Results from the breast cancer cohort of the phase II MOVIE study.

Duprez team

Assessment of Systematic JAK2V617F Screening in 996 Patients With Venous Thromboembolism. Ectopic expression of BEX genes in T-cell Acute Lymphoblastic Leukemia.

De Sepulveda team

Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML.

Team Aurand-Lions

Junctional adhesion molecule-C: A multifunctional mediator of cell adhesion.

Translate-it Department

Team Dusetti / Iovanna

Toward Precision Chemotherapy for Pancreatic Cancer Guided by Transcriptomic Signatures. The mitochondrial catastrophe induced by NUPR1 inhibitors as a novel strategy to fight against cancer. Mechanisms of induced resistance to the antitumoral agent ZZW-115 in pancreas ductal adenocarcinoma. Understanding the heterogeneity of pancreatic ductal adenocarcinoma. The intrinsically disordered protein NUPR1 binds to phospholipids. Self-assembling dendrimer nanodrug formulations for decreased hERG-related toxicity and enhanced therapeutic efficacy.

Benzekry / Ciccolini team

Dihydropyrimidine Dehydrogenase-Guided Dosing of 5-Fluorouracil: Prioritizing Precision Over Dose Reduction. Cross-Species Extrapolation of Neonatal Fc Receptor (FcRn) Binding Affinity to Predict Monoclonal Antibody Pharmacokinetics in Humans Using Physiologically Based Pharmacokinetic Modeling (PBPK): Are We There Yet? [Autoimmune diseases and immunotherapies]. DPD Ultra-Rapid Metabolizer Status and Efficacy of 5-Fluorouracil Treatment: A Real-World Study.

Mamessier / Bertucci team

Expression of antibody-drug conjugate targets in soft tissue sarcomas. Gene expression-based rationale for investigating CDK4/6 inhibitors in primitive myelofibrosis. Is adjuvant chemotherapy beneficial in NSCLC patients over 75? Insights from a retrospective analysis.

Team Pasquier / André

Near Complete Response With Trastuzumab Deruxtecan in a Teenager With Relapsing Metastatic Desmoplastic Small Round Cell Tumor.

Genome integrity department

Team Lachaud

TERT expression attenuates metabolic disorders in obese mice by promoting adipose stem and progenitor cell expansion and differentiation.

Pagès team

The RecBC complex protects single-stranded DNA gaps during lesion bypass.

The Coulon team

[Towards an ever more precise, integrated, and anticipatory management of breast cancer]. Toxicity Profiles of Antibody-Drug Conjugates: Synthesis and Graphical Insights to Optimize Patient-Centered Treatment Strategies for HER2-Negative Metastatic Breast Cancer. [Antibody-drug conjugates in breast cancer: Resistance mechanisms and prospects]. [Breast cancer in women of childbearing age: Issues surrounding the role of hormones].

COMET Department

Team Maina

Establishment of a mouse hepatocellular carcinoma tumoroid panel recapitulating inter- and intra- heterogeneity for disease modelling and combinatorial drug discovery. The HDAC inhibitor romidepsin renders liver cancer vulnerable to RTK targeting and immunologically active.

Team Charafe / Ginestier

The interplay of DNA damage, epigenetics and tumour heterogeneity in driving cancer cell fitness. The LRP4/YAP axis drives the radiation-tolerant persister (RTP) cell state in breast cancer.

Team Zimmermann

Syntenin Controls Extracellular Vesicle-Induced Tumour Migration by Regulating the Expression of Adhesion Proteins on Small Extracellular Vesicles.

Immunomonitoring platform

Robot-Assisted Surgery in Endometrial Cancer: A Dual Benefit for Patients and Surgeons.