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Abstract :
In myeloid leukaemias, the rapid clonal expansion of leukemic cells in the bone marrow leads to alterations of microenvironment properties, and reduction of the overall availability for each cell type in the constrained space of the medullar niche. In addition, bone marrow fibrosis that often occurs in myeloid leukemias induces physical modifications of the microenvironment. Reciprocally, the leukemic niche through a symmetrical mechanic response can also affect the intrinsic stiffness of leukemic cells. Therefore, our goal is to understand how leukemic bone marrow microenvironment can support leukemic progression or alter treatment response in myeloid malignancies. For this purpose, we use a standardized 3D human co-culture model, which allows maintenance of hematopoietic stem cells capacities, to track CML leukemic stem cells dormancy upon treatment. In addition, we have identified that resistant AML cells harbors different intrinsic rigidities and mechanotransduction pathways activation compared to sensitive cells. Our current strategy includes study of the interplay between leukemic cells and extracellular matrices of different natures (composition and stiffness) and usage of a soft cell confinement system.
Selected Publications:
– Voeltzel T*, Fossard G, Degaud M, Geistlich K, Gadot N, Jeanpierre S, Mickaelian I, Brevet M, Anginot A, Le Bousse-Kerdiles MC, Trichet V, Lefort S*, Maguer-Satta V*. A minimal standardized human bone marrow microphysiological system to assess resident cell behavior during normal and pathological processes. Biomaterials Science. 2022 Jan 18;10(2):485-498.
– Lefort S, El-Naggar A, Tan S, Colborne S, Negri GL, Pellacani D, Hirst M, Gusterson B, Morin GB, Sorensen PH, Eaves CJ. De novo and cell lines models of human mammary cell transformation reveal an essential role for Yb-1 in multiple stages of human breast cancer. Cell Death Differ. 2022 Jan; 29(1):54-64.
– Jeanpierre S, Arizkane K, Thongjuea S, Grockowiak E, Geistlich K, Barral L, Voeltzel T, Guillemin A, Gonin-Giraud S, Gandrillon O, Nicolini FE, Mead A, Maguer-Satta V*, Lefort S*. The quiescent fraction of chronic myeloid leukemic stem cells depends on BMPR1B, Stat3 and BMP4-niche signals to persist in patients in remission. Haematologica. 2021 Jan 1 ;106(1) :111-122.
– Prunet A, Lefort S, Delanoë-Ayari H, Laperrousaz B, Simon G, Saci S, Argoul F, Guyot B, Rieu J-P, Gobert S*, Maguer-Satta V*, Rivière C*. Development of a soft cell confiner to decipher the impact of mechanical stimuli on cells. Lab Chip. 2020 Nov 7 ;20(21) :4016-4030
– Bulaeva E, Pellacani D, Nakamichi N, Hammond C.A, Beer P.A, Lorzadeh A, Moksa M, Carles A, Bilenky M, Lefort S, Shu J, Wilhelm B.T, Weng A.P, Hirst M, Eaves C.J. MYC-induced human acute myeloid leukemia requires a continuing IL3/GM-CSF co-stimulus. Blood. Dec 10 ;136(24) :2764-2773.
– Lefort S*, Balani S, Pellacani D, Guyot B, Gorski SM, Maguer-Satta V, Eaves CJ. Monitoring autophagy heterogeneity in normal and de novo transformants of human mammary cells. Sci Rep. 2020 Nov 20 ;10(1) :20266
– Lefort S*, Tan S, Balani S, Rafn B, Hirst M, Eaves CJ. Initiation of human mammary cell tumorigenesis by mutant KRAS requires YAP inactivation. Oncogene. 2019 Nov 26.
– Voeltzel T, Flores-Violante M, Zylbersztejn F, Lefort S, Billandon M, Jeanpierre S, Joly S, Fossard G, Milenkov M, Mazurier F, Nehme A, Belhabri A, Paubelle E, Thomas X, Michallet M, Louache F, Nicolini FE, Caron de Fromentel C, Maguer-Satta V. A new signaling cascade linking BMP4, BMPR1A, ΔNp73 and NANOG impacts on stem-like human cell properties and patient outcome. Cell Death Dis. 2018 Sep 27;9(10):1011.
– Lefort S, Thuleau A, Kieffer Y, Sirven P, Bieche I, Marangoni E, Vincent-Salomon A, Mechta-Grigoriou F. CXCR4 inhibitors could benefit to HER2 but not to triple-negative breast cancers patients. Oncogene 2017 Mar 2;36(9):1211-1222. doi: 10.1038.
– Nguyen LV*, Pellacani D*, Lefort S, Kannan N, Osako T, Makarem M, Cox CL, Kennedy W, Beer P, Carles A, Moksa M, Bilenky M, Balani S, Babovic S, Sun I, Rosin M, Aparicio S, Hirst M, Eaves CJ. Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells. Nature. 2015 Dec 10; ;528(7581):267-71.
– Lefort S*, Joffre C*, Kieffer Y, Givel AM, Bourachot B, Zago G, Bieche I, Dubois T, Meseure D, Vincent-Salomon A, Camonis J, Mechta-Grigoriou F. Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers. Autophagy. 2014;10(12):2122-42.
Mini Bio:
Tout au long de mes travaux de recherche, j’ai cherché à identifier des mécanismes intrinsèques et extrinsèques essentiels à l’homéostasie, à l’initiation et la progression tumorale. Ainsi durant mon PhD (2005-2009), j’ai identifié des mécanismes consécutifs à l’infection par KSHV permettant l’établissement de la pathologie et de la tumorigénèse. J’ai ensuite rejoint l’Institut Curie (2009-2013), où mes travaux ont permis d’identifier des cibles thérapeutiques tumorales ou microenvironnementales spécifiques de sous−types de cancer du sein. Au sein du laboratoire Terry Fox (2014-2017), mes travaux sur les cellules souches et progénitrices mammaires humaines ont permis d’étudier le rôle de plusieurs déterminants moléculaires, tels que YB−1 et YAP, impliqués dans l’initiation tumorale. Ayant rejoint le CRCL en 2017, je m’intéresse dorénavant au rôle des contraintes mécaniques, via les éléments mécanosenseurs BMP et YAP, dans le maintien des cellules souches hématopoïétiques et leucémiques via leur interaction avec leur microenvironnement.
