CMTM6 stabilizes PD-L1 expression and refines its prognostic value in tumors.
Mamessier E, Birnbaum DJ, Finetti P, Birnbaum D, Bertucci F
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The Marseille Cancer Research Center celebrates its 50th anniversary ! -
Our team brings together multidisciplinary profiles to work on the development of tools that will ensure a better management and treatment of aggressive solid tumors (metastatic breast and colon cancers).
Our scientific priority is to tackle breast and colon metastatic cancers that are aggressive or resistant to treatments. This topic is addressed through four ambitious projects (i.e. Figure 1):
- A better classification of tumors and identification of predictors of resistance or response to treatments (at the bulk and single cell levels),
- The establishment of relevant pre-clinical models that recapitulate resistance or response to treatment, and can be used as a screening to tool to identify the best therapy for a given tumor,
- The use of liquid biopsies as a quasi-non-invasive tool to anticipate tumor progression/resistance occurrence,
- The design of new therapies for tumors aggressive or resistant to other treatments.
Figure 1. General workflow
To give the general direction to these projects, the team is headed by F Bertucci (pioneer in tumor profiling, medical oncologist and head of the translational research committee at the Paoli Calmettes Institute) and E Mamessier (Researcher at INSERM, cellular biologist, immunologist and expert at setting translational studies). This co-leadership allows to combine technical development and breaking new scientific topics with relevant clinical questions and access to patients’ samples.
The completion of each project is feasible thanks to the support of 18 additional people, each gifted in a specific discipline (bioinformatics, immunology, molecular biology, cellular biology, biochemistry…), so that they can work on most problematics, independently of the type of treatment.
In addition, the team is fully equipped with next generation sequencing (Nextseq500), pan-transcriptomic (Affymetrix), array-based comparative genomic hybridization (Agilent), circulating tumor DNA (BioRad) or Circulating tumor cells isolation (Parsortix and micromanipulator) platforms, and microfluidic devices (Ibidi, Fluigent, ..), Live Cell Imaging System, cell culture rooms dedicated to the processing of human samples… (i.e. Figure 2).
Altogether, we develop precision medicine strategies based upon better classification of tumors, more therapeutic options, better targeting and better comprehension of the mechanisms of resistance to treatments.
Come and join us in this adventure !
Figure 2. All techniques/technologies used in the team are designed to fit with patients’ samples and to meet clinical needs: Profiling and classification of tumors, single cells resolution caomputational approaches, multiplexed-immunofluorescence from FFPE tissues, Patient tumor derived organoids (simple or complex co-cultures), liquid biopsies analysis, identification of new targets and design of new treatments.
Keywords
- Resistance to treatment
- Aggressive cancers
- Antibody drug conjugates
- Circulating Tumor cells
- Tumoral Microenvironment
As one of the main translational research teams of the CRCM, one of our missions is to work around the major clinical issue in oncology, namely the progression of tumors that are resistant to treatments.
In this line, we design and launch prospective clinical trials to obtain timely samples (pre-, per- and post-treatment, and at progression), associated with the clinical data. This is particularly important for the most recent drugs, for which few data are available. The objective is to provide us with original and precious material that will allow us to address clinically relevant issues. These trials are national, uni-/multicentric, IPC/AP-HM-sponsored, and coordinated by medical doctors from our team.
To tackle the issue of resistance to treatments, we have orchestrated our research program around 4 axes.
Our 4 research axes
Tumor cells plasticity and dynamism of response to treatment
There are no or few consensual biomarkers of response/resistance reported for each treatment. One reason is the absence of resolutive analysis of timely samples (pre-, per- and post-treatment, and at progression) to identify the multiple mechanisms selected by the treatment. This was due to technical limitation that have now been overcome with recent technologies (RNAseq from small, degraded and formalin-fixed samples) or preclinical models (patient-derived tumor organoids, patient-derived xenografts…) that we are developing in the laboratory. These topics are addressed in the Tumor profiling and the Preclinical models groups. For more info, contact F Bertucci, E Mamessier, and O Cabaud
Role of intra-tumor heterogeneity in treatment response
Tumor cells composing a tumor are heterogeneous and this heterogeneity might not be targetable with one drug only. Untouched cells will further initiate new tumors. The first program is in charge to evaluate this heterogeneity in various cancer types and at different stages (bulk and single cell characterization), provide tools to measure the degree of heterogeneity at individual level (multiplexed immunofluorescence of tumor cells and its micro-environment), and propose new markers and treatment combination strategies to overcome this heterogeneity (computational analysis, in vitro / in vivo assays). This topic is addressed in the Tumor heterogeneity in space and time group. For more info, contact F Bertucci, E Mamessier and E Denicolaï.
Early detection of treatment resistance using liquid biopsies
The earliest the resistance to a treatment is detected, the faster the clinician can act and propose an ad-hoc strategy. We are looking for new markers of resistance to treatment using liquid biopsies, which are quasi non-invasive methods that give access to tumor material with only few milliliters of blood. This topic is addressed in the Circulating tumor cells group. For more info, contact E Mamessier and E Denicolaï.
Providing new treatments for aggressive tumors
When a tumor become resistant to a treatment, the new problem is to tackle the mechanism of resistance so that the initial treatment can be efficient again (durable response). We have shown this proof-of-concept in vivo, in a pre-clinical model, without adding additional toxicity due to the supplementary drug. We will continue to identify treatments that comply with this objective. This topic is addressed in the New therapeutic strategies and the Preclinical models groups. For more info, contact F Bertucci, E Mamessier, O Cabaud and M Lopez.
OncoPredic’Team in June 2023
OncoPredic’Team at the LMDF charity run for patients
Team publications
Take Home Message
the Team publications
NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non-inflammatory breast cancers.
Bertucci F, Rypens C, Finetti P, Guille A, Adélaïde J, Monneur A, Carbuccia N, Garnier S, Dirix P, Gonçalves A, Vermeulen P, Debeb BG, Wang X, Dirix L, Ueno NT, Viens P, Cristofanilli M, Chaffanet M, Birnbaum D, Van Laere S
A Tyrosine Kinase Expression Signature Predicts the Post-Operative Clinical Outcome in Triple Negative Breast Cancers.
de Nonneville A, Finetti P, Adelaide J, Lambaudie É, Viens P, Gonçalves A, Birnbaum D, Mamessier E, Bertucci F
Sensitive and easy screening for circulating tumor cells by flow cytometry.
Lopresti A, Malergue F, Bertucci F, Liberatoscioli ML, Garnier S, DaCosta Q, Finetti P, Gilabert M, Raoul JL, Birnbaum D, Acquaviva C, Mamessier E
Molecular classification as prognostic factor and guide for treatment decision of pancreatic cancer.
Birnbaum DJ, Bertucci F, Finetti P, Birnbaum D, Mamessier E
Dual Programmed Death Receptor-1 and Vascular Endothelial Growth Factor Receptor-2 Blockade Promotes Vascular Normalization and Enhances Antitumor Immune Responses in Hepatocellular Carcinoma.
Shigeta K, Datta M, Hato T, Kitahara S, Chen IX, Matsui A, Kikuchi H, Mamessier E, Aoki S, Ramjiawan RR, Ochiai H, Bardeesy N, Huang P, Cobbold M, Zhu AX, Jain RK, Duda DG
Liquid Biopsies for Ovarian Carcinoma: How Blood Tests May Improve the Clinical Management of a Deadly Disease.
Mari R, Mamessier E, Lambaudie E, Provansal M, Birnbaum D, Bertucci F, Sabatier R
CD25high Effector Regulatory T Cells Hamper Responses to PD-1 Blockade in Triple-Negative Breast Cancer.
Fattori S, Le Roy A, Houacine J, Robert L, Abes R, Gorvel L, Granjeaud S, Rouvière MS, Ben Amara A, Boucherit N, Tarpin C, Pakradouni J, Charafe-Jauffret E, Houvenaeghel G, Lambaudie E, Bertucci F, Rochigneux P, Gonçalves A, Foussat A, Chrétien AS, Olive D