Team
RNA splicing, Cell signaling and Response to Therapies

Dpt: Microenvironment, cell plasticity and signalling

Our research activities

Deep-sequencing of human transcriptome has provided evidence that up to 90% of human multi-exons genes undergoes pre-mRNA alternative splicing. This last decade, the development of high-throughput transcriptomic analyses has unravelled the existence of thousand cancer-specific splicing patterns which distinguish between tumor types, sub-types and/or clinical stages. Although these data clearly establish a link between massive deregulation of pre-mRNA alternative splicing and cancer, its functional consequences in cancer etiology, progression and response to therapies still remain largely unknown. Our team project aims to dissect the molecular bases by which alternative splicing reprogramming contributes to the adaptative response and therapeutic resilience of lung cancer cells, and thereby concurs to their highly agressive features and to the poor prognosis of lung cancer patients. We expect the characterization of key splicing reprogramming events that govern lung cancer cell plasticity and drug adaptability to pave the way for the definition of new paradigms in lung cancer biology, and for the development of innovative therapeutic strategies aimed at reorientate dysregulated RNA splicing to tackle therapeutic resilience. Our scientific activities combine basic science and translational research thanks to a close partnership between biologists and clinicians belonging to the lung cancer field.
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Béatrice EYMIN

Team leader

04 76 54 94 76

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Our research axes

SR proteins are critical splicing factors. We previously showed that SR proteins are up-regulated in lung tumors. Our objectives are to deepen the molecular mechanisms by which SR proteins contribute to lung tumor progression and response to therapies. More specifically, we want to decipher whether and how SR proteins contribute to genomic instability and mutations in lung cancer cells which occur during therapeutic resilience through modulation of the DNA Damage Response and DNA repair pathways.

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Pharmacological inhibitors targeting different components of the spliceosome machinery constitute a promising therapeutic area in cancer. However, the molecular mechanisms supporting their anti-cancer effects remain largely unknown. Our objectives are to decipher whether the use of these inhibitors, either alone or in combination with chemotherapies, could be a way to counteract drug resistance in lung cancer.

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Receptor Tyrosine Kinases (RTK) including the Epidermal Growth Factor Receptor (EGFR) play a key role in lung cancer progression. The use of tyrosine kinase inhibitor of EGFR (EGFR-TKI) is a very promising therapeutic approach with unprecedent results on patients survival. However despite its proven efficacy, resistance inevitably develops. Our objectives are to evaluate the contribution of RNA splicing reprogramming to the development of acquired resistance to EGFR-TKI in NSCLC.

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Circular RNAs (circRNAs) belong to a new category of mostly non-coding RNAs which are very stable and detectable in liquid biopsies, making them promising biomarkers. In recent years, their role in the initiation and progression of cancers as well as in the response to treatment has emerged. However, the molecular mechanisms underlying their effects remain largely unknown. Our objectives are to deepen the role of circRNAs in the escape of lung tumors to treatment.

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Our major publications

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Altered splicing of ATG16-L1 mediates acquired resistance to Tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer

Hatat A.S., Benoit-Pilven C., Pucciarelli A., De Fraipont F., Lamothe L., Perron P., Rey A.,…

Mol Oncol 2022 16 :3490-3508 doi: 10.1002/1878-0261.13229

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FGF-2 promotes angiogenesis through a SRSF1/SRSF3/SRPK1-dependent axis that controls VEGFR1 splicing in endothelial cells

Jia T, Jacquet T, Dalonneau F, Coudert P, Vaganay E, Exbrayat-Héritier C, Vollaire J, Josserand…

BMC Biology 2021 19(1):173. doi: 10.1186/s12915-021-01103-3

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VEGF165b, a splice variant of VEGF-A, promotes lung tumor progression and escape from anti-angiogenic therapies through a β1 integrin/VEGFR autocrine loop

Boudria A, Abou Faycal C, Jia T, Gout S, Keramidas M, Didier C, Lemaitre N,…

Oncogene 2019 38(7):1050-1066 doi: 10.1038/s41388-018-0486-7

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Heteromultivalent targeting of integrin avb3 and neuropilin 1 promotes cell survival via the activation of the IGF-1/insulin receptors

Jia T, Choi J, Ciccione J, Henry M, Mehdi A, Martinez J, Eymin B, Subra…

Biomaterials 2018 155:64-79 doi: 10.1016/j.biomaterials.2017.10.042

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Nuclear translocation of IGF-1R by intracellular amphiregulin contributes to the resistance of lung tumor cells to EGFR-TKI

Guerard M, Robin T, Perron P, Hatat A.S, David-Boudet L, Busser B, Coll J.L, Lantuejoul…

Cancer Letters 2018 420:146-155 doi: 10.1016/j.canlet.2018.01.080

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The sVEGFR1-il3 splice variant regulates a beta1 integrin/VEGFR autocrine loop involved in the progression and the responce to anti-angiogenic therapies of squamous cell lung carcinoma

Abou Faycal C, Brambilla E, Agorreta J, Lepeltier N, Jacquet T, Lemaitre N, Emadali A,…

British Journal of Cancer 2018 118 :1596-1608 doi: 10.1038/s41416-018-0128-4. 

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Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival

Dayde D, Guerard M, Perron P, Hatat A.S, Barrial C, Eymin B and Gazzeri S.

Oncogene 2016 35(30):3986-94. doi: 10.1038/onc.2015.480.

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p14ARF inhibits the growth of lung adenocarcinoma cells harboring an EGFR L858R mutation by activating a STAT3-dependent pro-apoptotic signalling pathway

Ozenne P, Dayde D, Brambilla E, Eymin B and Gazzeri S.

Oncogene 2013 32(8):1050-8 doi: 10.1038/onc.2012.107. 

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Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin

Edmond V, Moysan E, Khochbin S, Matthias P, Brambilla C, Brambilla E, Gazzeri S and…

EMBO J 2011 30(3):510-23 doi: 10.1038/emboj.2010.333

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E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

Merdzhanova G, Edmond V, De Seranno S, Van Den Broeck A, Corcos L, Brambilla C,…

Cell Death Diff 2008 15 :1815-1823 doi: 10.1038/cdd.2008.135.

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Our activities in pictures

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Our collaborations

  • Pr Ester Hamond (Institute for Radiation Oncology, Oxford, United Kingdom)
  • Dr Pablo Huertas (Andalusian Molecular Biology and Regenerative Medicine Centre, CABIMER, Seville, Spain)
  • Dr Eleni Nikolakaki (Laboratory of Biochemistry, Aristotelian University, Thessaloniki, Greece)
  • Dr Didier Auboeuf (ENS, Lyon)
  • Dr Didier Decaudin (Institut Curie, Paris)
  • Dr Martin Dutertre (Institut Curie, Paris)
  • Dr Carmen Garrido (U1231, Dijon)
  • Pr Nicolas Girard (Institut Curie/Montsouris, Paris)
  • Dr Antonio Maraver (IRCM, Montpellier)
  • Dr Franck Mortreux (ENS, Lyon)
  • Dr Olivier Sordet (CRCT, Toulouse)

Our technologies

  • 2D and 3D cell culture
  • Proximity Ligation assay (PLA)
  • RNA BaseScope
  • RNA sequencing
  • RT/PCR and quantitative PCR (QPCR)
  • JESS
  • Western blotting
  • DNA Fiber assay
  • Immunoprecipitation
  • GST-pull down
  • Immunofluorescence and Immunohistochemistry
  • Flow cytometry
  • Seahorse
  • SIRF