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Période 2020-2022 : Ievgenia Pastushenko

ACADEMIE ROYALE DE MEDECINE DE BELGIQUE
SEANCE DE REMISE DES PRIX 2020 et 2021
Le 11 septembre 2021
PRIX LESLIE GENTIL 2021


Le Prix Leslie Gentil est décerné pour la première fois. Il récompense une recherche clinique ou fondamentale en cancérologie de la peau et du mélanome, en particulier.

Deux candidatures de très grande qualité ont été soumises à l'Académie pour le Prix 2021.

Après une délibération en mode virtuel, le jury, composé des Professeurs Del Marmol, Poumaye et de moi-même, a proposé à notre Compagnie d'attribuer le Prix Leslie Gentil à Madame
Levgenia Pastushenko pour son mémoire intitulé : « Mechanisms of skin cancer progression, metastasis and resistance to therapy ».

Madame Pastushenko a été proclamée « Médecin » en 2009 et « Docteure en sciences biomédicales » en 2014 à l' Université de Saragosse en Espagne.
Elle est agréée spécialiste en dermatologie depuis 2014.

En 2015, Madame Pastushenko entame des recherches fondamentales en cancérologie dans le Laboratoire du Professeur Cédric Blanpain à l' Université libre de Bruxelles, bénéficiant
successivement d'une bourse Télévie du FNRS, d'une bourse clinique du FNRS et d'un mandat de la Fondation contre le Cancer.

Durant ces cinq années de recherche, Mme Pastushenko a mis en exergue un nouveau concept en mettant en évidence les étapes de transformation d'une cellule épithéliale en une cellule
mésenchymateuse tumorale ainsi que le mécanisme génique sous-jacent, menant ainsi à d'intéressantes perspectives thérapeutiques.

Il s'agit d' avancées majeures dans la connaissance des cancers cutanés rapportées dans plusieurs publications récentes dont deux articles dans Nature. Madame Pastushenko en est la
première auteure.

Mme Pastushenko a fait preuve d'une grande curiosité scientifique dès l'entame de sa carrière comme en témoignent ses publications initiales concernant des aspects anatomo-cliniques
des cancers de la peau et du mélanome.

Cette carrière est un bel exemple de recherche translationnelle menée par une clinicienne –chercheuse dont l'avenir scientifique semble être des plus prometteurs.

Nous adressons nos félicitations les plus chaleureuses à la lauréate.

 

Prof Ronald Kramp
Président du jury

THE LESLIE GENTIL PRIZE

Ievgenia Pastushenko, MD, PhD

Mechanisms of skin cancer progression, metastasis and resistance to therapy


Non-melanoma skin cancer is the most frequent type of cancer worldwide. One in five adults will develop skin cancer by the age of 70. The majority of non-melanoma skin cancers have good prognosis. However, up to 5% of patients with squamous cell carcinoma of the skin will develop metastasis and will eventually die as a consequence of the metastasis disease. During the last years, I focused my research on understanding the mechanism of squamous cell carcinoma progression, metastasis and therapy resistance. I showed that tumor cells are not homogeneous, and that the tumors are composed by subpopulations of tumor cells with different functions. I uncovered that tumor cells that exhibit an hybrid epithelial-to-mesenchymal transition (EMT)  phenotype (tumor cells that simultaneously express epithelial and mesenchymal markers), are responsible for the majority of the metastasis. I further uncovered that mutations in the gene called FAT1, one of the most frequently mutated genes in a wide range of cancer types, promote and stabilize this highly metastatic hybrid EMT phenotype and I discovered the precise molecular mechanisms regulating phenotype. I showed that loss of FAT1 promotes simultaneous activation of two opposite programs: an EMT program through CAMK2-SRC-YAP1 signaling pathway and an epithelial program through CAMK2-EZH2-SOX2 pathways, thus stabilizing tumor cells in hybrid EMT phenotype. Very importantly, based on these mechanistic discoveries, I identified drug resistance and vulnerabilities in FAT1-deficient tumors. I showed that FAT1 mutated cancers are resistant to EGFR inhibitors (drugs frequently used to treat metastatic squamous cell carcinomas), while they are sensitive to SRC-inhibitors (drugs used only for treatment of blood cancers). The results of this research have very important implications for our understanding of cancer biology, as well as have immediate applications for personalized treatment of patients with cancers harboring mutations in FAT1.

 

 

ACADEMIE ROYALE DE MEDECINE DE BELGIQUE
SEANCE DE REMISE DES PRIX 2020 et 2021
Le 11 septembre 2021
PRIX LESLIE GENTIL 2021

 

La médaille de l'Académie est décernée à Monsieur Panagiottos Karras, Docteur en biologie moléculaire, pour son mémoire intitulé : « A developmental cellular hierarchy in melanoma uncouples growth and metastatic phenotypes » et rapportant des résultats novateurs observés dans un modèle murin reproduisant le mélanome.

Toutes nos félicitations à Mr Karras.

 

Prof Ronald Kramp
Président du jury

Brief description of the project

Melanoma is notorious for its high degree of intra-tumor heterogeneity (ITH), a feature associated with therapy resistance and poor clinical outcomes. ITH can have a genetic origin. Moreover, cancer cells with the same genome can switch back and forth between different phenotypic states, a phenomenon referred to as phenotype switching. Such changes result from microenvironmental cues and/or treatment-imposed selective pressures and are often driven by stochastic epigenetic and/or transcriptional fluctuations. Finally, the cancer stem cell model provides an additional explanation for the phenotypic and functional heterogeneity among cancer cells. The model posits that tumors are hierarchically organized into subpopulations of tumorigenic cancer stem cells (CSCs) and their non-tumorigenic progeny. It has been suggested that CSCs may drive tumor growth, metastasis and therapy resistance, making them attractive cancer targets. Although CSCs have been identified and extensively characterized in a number of solid and hematopoietic malignancies, the existence of Melanoma Stem Cells (MSCs) has been under ongoing debate mainly due to the lack of relevant pre-clinical models and unbiased high-throughput technologies that allow profiling of individual cells and their spatio-temporal mapping.
Our data demonstrate that the transcriptomic landscape of both mouse and human melanoma is richer than previously reported and it can be fully recapitulated in lesions arising in NRAS-mutant mice (Karras et al., under revision). Spontaneous melanoma tumours arising in mice carrying the Tyr::NrasQ61K/° allele and lacking p16INK4a (Ink4a) were collected and subjected to single-cell RNA sequencing (scRNA-seq). Cross-species analyses identified novel and evolutionarily conserved melanoma states, including a highly de-differentiated melanoma stem cell-like state (MSCs). This MSCs state bears similarity with the (pre-EMT) neural crest stem cell population, which is still in contact with the neural tube and sits at the apex of the neural crest lineage. This observation raised the possibility that this population of melanoma cells may be sitting at the top of a cellular hierarchy established in these melanoma lesions, and thereby function as MSCs. To test this possibility, an inducible multicolour lineage tracing approach based on to fate map at clonal density melanoma cells was used. Strikingly, clonal analyses coupled with proliferation kinetics and mathematical modelling provided strong evidence of a cellular hierarchy during melanoma growth. This behaviour was consistent with a proliferative hierarchy in which a stem cell-like population (S) expands stochastically through duplication giving rise to a progenitor cell state (P). The predicted frequency of the S population was broadly consistent with the proportion of the putative MSC population identified by scRNA-seq. Importantly, almost every single productive clone (in contrast to unproductive clones of < 5 cells) were in close contact with blood vessels, indicating that melanoma cells fueling primary tumor growth may localize preferentially to a perivascular niche. The NicheNet algorithm, an unbiased computational approach that predicts cell-to-cell communications by inferring ligand-receptor interactions from single-cell transcriptomic data, predicted crosstalk between endothelial cells and the putative melanoma MSC population. Particularly, NicheNet predicted that this crosstalk is mediated by the Dll4 (ligand) and Notch3 (receptor), which are expressed in endothelial cells and the MSCs, respectively. The existence of this pre-EMT NC cell state was further confirmed in human biopsies by performing single cell RNA seq in drug naïve melanoma patients, and spatially by immunostaining lesions from primary melanomas.
Interestingly, single cell profiling revealed a distinct melanoma state that exhibited mesenchymal-like (EMT) features. Unsupervised in silico analyses predicted the Prrx1 Transcription Factor (TF) as a putative driver of this state. Functional studies confirmed a role of PRRX1 in melanoma metastasis. Importantly, in vivo fate mapping demonstrated that PRRX1 melanoma cells were found to be preferentially located deep in the dermis, at the invading front, while once reaching distant organs they lose PRRX1 expression supporting an EMT continuum. This cell state may represent a potential population of metastatic initiating cells (MICs).
Altogether, these data suggest that melanoma growth is fueled by a population of MSCs population that accumulate around blood vessels whereas metastasis is presumably driven by a mesenchymal population of MICs.