Hans-Guido Wendel: Overview
The main areas of research in the lab are:
We have established a genetically and pathologically accurate model of follicular lymphoma that allows us to discover and characterize genetic drivers of lymphoma development, disease progression, and determinants of therapeutic success in vivo.
Recent examples of this disease-centered work on lymphoma include:
The identification of the ephrin receptor A7 (EPHA7) tumor suppressor in lymphoma and the development of bi-functional anti-CD20-EPHA7 antibodies that restore EPHA7 function in CD20 positive lymphomas (Oricchio et al., Cell, 2011)
Characterization of the molecular targets of key epigenetic regulators in lymphoma including MLL2/KMT2D, CREBBP, and EP300 (Ortega et al., Nat. med. 2015, Cancer Discovery 2016)
Discovery that the HVEM-BTLA immune receptor interaction is disrupted in some ~75% of follicular lymphomas, and generation of CAR-T cell “micro-pharmacies” that produce and secrete the HVEM ligand at the tumor site (Boice et al., Cell 2016).
Ongoing lymphoma studies build on emerging immunotherapies and use Crispr/Cas screens to uncover novel therapeutic vulnerabilities.
Some of our key collaborators include Anas Younes (MSKCC), Ari Melnick (Weill Cornell), Renier Brentjens (MSKCC), Brian Chait and Mike Rout (Rockefeller University), Randy Gascoyne (UBC, Canada), Karin Tarte (U. Rennes, France).
The translation of mRNAs into protein is abnormally increased in most if not all cancers and this is a direct consequence of oncogenic mutations, indicating that aberrant translation is an integral part of cancer biology. In principle, increased translation may simply satisfy the metabolic needs of proliferating cells, alternatively activation of specific mRNA translation programs may actively drive malignant growth. Examples of our work in mRNA translation in cancer include:
Translation factors can drive cancer development. Increased levels of the initiation factor eIF4E, as seen in human cancers, causes lymphomas in vivo (Wendel et al., Nature 2004).
EIF4E’s oncogenic function activity requires phosphorylation by the eIF4E kinase MNK1/2. This pinpoints MNK1/2 as a new drug target in cancer (Wendel et al., Genes & Dev. 2007).
Cancer cells activate defined oncogenic mRNA translation programs. For example, the RNA helicase eIF4A is upregulated in cancer and drives the translation of oncogenic mRNAs such as MYC that are marked by RNA G-quadruplex sequences (Wolfe et al., Nature 2014).
Inhibitors of eIF4A block the translation of MYC and other cancer genes and show exciting activity against several cancers (Wolfe et al., Nature 2014).
Ongoing work explores immediate mRNA translation responses to various stimuli. We speculate that interactions between defined RNA motifs and binding proteins encode specific translational responses.
Ongoing projects in the lab explore these responses using deep RNA sequencing, ribosome footprinting, and RNA structure probing.
Key collaborators include Zhengqing Ouyang (The Jackson Lab), Gunnar Raetsch (ETH Zurich), Hemali Phatnani (NY Genome Center), Derek Tan (MSKCC), Leemor Joshua-Tor (CSHL). We also work with drug makers Takeda/the Tri-institutional Drug Discovery Institute and Glaxo Smith Kline.