Death receptors signalling and cancer therapy

 

 Selected Key words:  cell death and survival signaling, colorectal cancer, membrane receptors dynamics, transport and sorting mechanisms, live cell imaging.

 Research project:  Alterations in the control of cell survival and death contribute to the pathogenesis of many human diseases. In particular, the dysfunction in the signaling cascade leading to the programmed cell death (apoptosis) has been shown as a key factor in the development of many types of cancer. Since the last ten years my lab is focused on the understanding of the role of one of these apoptotic pathways, probably the most studied thus far, the one triggered by Fas (TNFRSF6) upon its engagement by its ligand, Fas ligand (FasL). Accumulated evidence indicates that unlike most non-malignant cells, tumor cells have a markedly reduced susceptibility to FasL-induced Fas-mediated apoptosis. The alteration of the expression Fas or FasL not only can have significant effects on the ability of tumor cells to grow, metastasize, and damage host cells but also the ability to evade the immune system. Thus, the understanding of molecular mechanisms of Fas-mediated signaling is crucial for the development of cancer treatment strategies.

 

 Our initial working hypothesis  was that Fas interactions with its lipidic and proteic environment within the plasma membrane, before and upon FasL binding, is critical for its downstream signalling and thus its final outcome: death or survival and that disturbance of these interactions might contribute to tumorigenesis. Our main scientific results (listed below) allowed us to have a better understanding on the Fas-mediated cell death signalling pathways:

  • The study of the nanodomains (rafts) in Fas cell death signaling.
  • The study of the palmitoylation status and roles of death domain containing TNFRs members (Fas, TNFR1, the TRAIL receptors DR4 and DR5) and in the dependence receptors (DCC and UNC5H) signaling.
  • The demonstration of a CD95-glycosphingolipid interaction in cell death and survival signals.
  • The dissection of the molecular signaling pathways involved in the different cell death modes of triple-negative breast cancer cells induced by hexadecylphosphocholine (HePC/miltefosine), a clinically relevant anticancer alkylphosphocholine.
  • The identification of two proteases (ADAM10 and SPPL2a) implicated in FasL processing and their critical role in Fas/FasL signaling.

 Our actual aim  is to understand the versatility of the Fas receptor at the molecular level and its importance in the tumoral initiation and progression processes. Results in our laboratory show that triggering Fas signaling by sublethal doses of FasL can activate proteins with known survival and proliferative functions (e.g. Akt and MAPK), and induce colorectal cancer (CRC) cell proliferation. In addition, the evidence of Fas/FasL contribution in CRC metastasis is emerging. A multifaceted scenario has also been presented where CRC cells not only employ the anti-apoptotic and proliferative capacity of the Fas/FasL signaling for local growth but also utilize FasL to induce apoptosis in hepatocytes to facilitate the liver metastasis. In addition, invasion of CRC cells and liver metastasis promoted by activating Fas with FasL have been shown dependent on oncogenic K-Ras, one of the first gene mutations in CRC development. This thus links the Fas/FasL non-apoptotic signaling to major colorectal carcinogenesis pathways. Despite the fact that Fas signaling plasticity is central to the balance of life and death decision of the cell, the regulation of this versatility remains obscure. It is therefore a clear necessity to elucidate the mechanisms involved to achieve a better understanding of colorectal carcinogenesis and thus the development of effective CRC therapies.

 Methodologies used 
Multi-color live cell imaging; cell death and proliferation assays; gain and loss of function of colorectal cell lines; immunohistochemistry; inducible exogenous expression by lentiviral infection; TALEN technique; microRNAs.

 

Last publications

Site-Specific Detection of Tyrosine Phosphorylated CD95 Following Protein Separation by Conventional and Phospho-Protein Affinity SDS-PAGE. - 2017 - Methods in molecular biology (Clifton, N.J.) - 1557 P173-188 - Chakrabandhu K, Huault S, and Hueber,AO

Detection of S-Acylated CD95 by Acyl-Biotin Exchange. - 2017 - Methods in molecular biology (Clifton, N.J.) - 1557 P189-198 - Rossin A, and Hueber,AO

An Evolution-Guided Analysis Reveals a Multi-Signaling Regulation of Fas by Tyrosine Phosphorylation and its Implication in Human Cancers. - 2016 - PLoS biology - 14 Pe1002401 - Chakrabandhu K, Huault S, Durivault J, Lang K, Ta Ngoc L, Bole A, Doma E, Dérijard B, Gérard JP, Pierres M, and Hueber,AO

Fas Versatile Signaling and Beyond: Pivotal Role of Tyrosine Phosphorylation in Context-Dependent Signaling and Diseases. - 2016 - Frontiers in immunology - 7 P429 - Chakrabandhu K, and Hueber,AO

Dominant negative FADD dissipates the proapoptotic signalosome of the unfolded protein response in diabetic embryopathy. - 2015 - American journal of physiology. Endocrinology and metabolism - 309 PE861-73 - Wang F, Weng H, Quon MJ, Yu J, Wang JY, Hueber AO, and Yang,P

The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth. - 2015 - Nature - 522 P482-6 - Andersen DS, Colombani J, Palmerini V, Chakrabandhu K, Boone E, Rì¶thlisberger M, Toggweiler J, Basler K, Mapelli M, Hueber AO, and Léopold,P

Antitumor and cytotoxic properties of a humanized antibody specific for the GM3(Neu5Gc) ganglioside. - 2015 - Immunobiology - 220 P1343-50 - Dorvignit D, Garcì­a-Martì­nez L, Rossin A, Sosa K, Viera J, Hernández T, Mateo C, Hueber AO, Mesa C, and Lì³pez-Requena,A

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability. - 2014 - Cell death and differentiation - Rossin A, Durivault J, Chakhtoura-Feghali T, Lounnas N, Gagnoux-Palacios L, and Hueber,AO

Synergism of PI3K/Akt inhibition and Fas activation on colon cancer cell death. - 2014 - Cancer letters - 354 P355-64 - Zhu L, Derijard B, Chakrabandhu K, Wang BS, Chen HZ, and Hueber,AO

Interferon decreases VEGF levels in patients with chronic myeloid leukemia treated with imatinib. - 2014 - Leukemia research - 38 P662-5 - Legros L, Guilhot J, Huault S, Mahon FX, Preudhomme C, Guilhot F, Hueber AO, and ,

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Hueber Anne-Odile
Group Leader

2002 Prix Rosen de cancérologie

2001 ATIP CNRS

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Members Team
Researchers
   Derijard Benoit
   Gagnoux Laurent
   Rossin Aurélie
Clinical Researchers
   Benizri Emmanuel
   Legros Laurence
PreDocs
   Awina Hala
   Miloro Giorgia
   Ta Ngoc Ly
Engineers & Technicians
   Chakrabandhu Krittalak
   Huault Sébastien
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