Christof Fellmann’s lab focuses on unraveling organizational principles of cellular signaling networks in cancer progression and therapy. Fellmann’s work has centered on better understanding RNA-guided immune systems, including RNAi and CRISPR-Cas machinery, and leveraging them to dissect cancer, with a particular focus on RAS-mutant tumors and glioblastoma. His lab studies the mechanistic interplay between CRISPR‐Cas enzymes and mammalian DNA repair pathways to pioneer innovative approaches for genome manipulation and precision medicine. Fellmann and his team apply these methods to study the plasticity of cellular signaling networks and their rewiring in cancers, with the ultimate goal of translating insights into clinically actionable strategies to treat patients.
Areas of Expertise
Glioblastoma (GBM) is the most prevalent lethal primary brain tumor in adults and one of the most challenging cancers to treat. Despite multimodal treatment regimens including surgical resection, radio- and chemotherapy, the median survival of GBM patients remains only 12–15 months. GBMs are highly diffuse and exhibit extensive intratumoral heterogeneity, with subpopulations of cells displaying distinct mutations, copy number aberrations, gene expression patterns, and epigenetic states. This confounds diagnostic efforts and presents an opportunity for the cancer to evade therapy. Hence, there is an urgent need to establish innovative treatment strategies that can target and efficiently eliminate GBM cells in vivo irrespective of their mutational and epigenetic profile.
Fellmann and his team focus on understanding principles of cellular communication and its rewiring in brain cancer by pioneering synthetic biology tools and applying them to cell culture and in vivo models for the development of innovative, clinically actionable glioblastoma therapies. Specifically, CRISPR-Cas9 enzymes are RNA-guided DNA endonucleases enabling programmable introduction of DNA double-strand breaks at target loci throughout the genome. Their discovery and establishment as tools for genome editing and manipulation has revolutionized biomedicine. Yet, the translation of CRISPR-Cas technologies to clinical applications still faces a number of hurdles, including the possibility of off-target effects and the difficulty of in vivo delivery. Through their efforts to optimize the safety and flexibility of these methods, Fellmann and his team help unravel the complexities of cellular signaling and transform CRISPR-Cas from a tool for discovery to a therapeutic modality that can eventually be deployed for precision medicine.
Research Investigator, Gladstone Institutes
Assistant Adjunct Professor, Department of Cellular and Molecular Pharmacology, School of Medicine, UC San Francisco
Christof Fellmann holds an undergraduate degree (Vordiplom—B.Sc. equivalent) from the University of Basel, Switzerland, an engineering degree in biotechnology (Dipl. Ing. Biotech.—M.Sc. equivalent) from the Ecole Supérieure de Biotechnologie, Strasbourg, France, and a PhD in molecular life sciences from Cold Spring Harbor Laboratory, USA/University of Zurich, Switzerland.
Fellmann did his PhD work under the guidance of Dr. Scott Lowe at Cold Spring Harbor Laboratory, working on cancer modeling and large-scale screening. Developing high-throughput methods, he investigated mechanistic requirements of microRNA biogenesis (Fellmann et al., Mol Cell, 2011) and leveraged this insight to develop state-of-the-art RNAi tools (Fellmann et al., Cell Rep, 2013; Pelossof et al., and Fellmann, Nat Biotechnol, 2017). In turn, they used these tools to uncover signaling networks in RAS-mutant cancer (Yuan*, Fellmann*, Lee* et al., Cancer Discov, 2014), among others.
After establishing his own company building genetically engineered mouse models, Fellmann trained as a postdoctoral fellow with Jennifer Doudna at UC Berkeley, focusing on regulation of CRISPR-Cas enzymes, including circular permutation of Cas9 for precise fusion proteins and protease-activated ProCas9s for tissue-specific genome editing (Oakes*, Fellmann* et al., Cell, 2019). Concurrently, he deployed advanced CRISPR methods to discover synthetic lethal therapeutic dependencies in TERT-promoter mutant glioblastoma (Amen*, Fellmann* et al., in prep).
How Did You Get Your Start in Science?
“Curiosity to explore the unknown.”
Honors and Awards
2019 UCSF Brain Tumor SPORE Career Enhancement Program (CEP) award, NIH, National Cancer Institute (NCI).
2019 8th Annual Congress on Cancer Metastasis, San Francisco, USA, Invited talk
2019 Microbiology Society Annual Conference 2019, Belfast, UK, Prize medal lecture
2018 Cancer Research: A Joint Celebration Meeting, Instituto do Câncer do Estado de São Paulo (ICESP), São Paulo, Brazil, Keynote address
2017 American College of Rheumatology, Association of Rheumatology Health Professionals (ACR/ARHP), Annual Meeting, San Diego, USA, State-of-the-Art lecture
2017 Swiss Academy of Pharmaceutical Sciences, 10th Swiss Pharma Science Day, Bern, Switzerland, Plenary lecture
2017 Workshop on Pancreatic Cancer, Cold Spring Harbor Laboratory, Cold Spring Harbor, USA, Selected participant
2017 International Society for Heart and Lung Transplantation, 37th Annual Meeting and Scientific Sessions, San Diego, USA, Invited talk
2017 American Association for Cancer Research (AACR), Annual Meeting 2017, Washington, DC, USA, Invited speaker, educational session
2017 24th International Molecular Med Tri-Conference, San Francisco, USA, Invited talk
2016 NIH Pathway to Independence Award (K99/R00), NIH, National Institute of General Medical Sciences (NIGMS)
2016 American Transplant Congress, Annual Meeting 2016, Boston, USA, State-of-the-Art address
2015 Discovery On Target, New Frontiers in Gene Editing, Boston, USA, Invited talk
2015 11th KOGO Winter Symposium, Korea Genome Organization, Hongcheon, Korea, Invited talk
2014 Translational Cancer Research for Basic Scientists workshop, AACR, Dana-Farber Cancer Institute/Harvard Cancer Center, Boston, USA, Selected participant
2014 RNA Silencing, Keystone Symposia, Seattle, USA,Invited talk
2013 8th Microsymposium on Small RNAs, IMBA, Vienna, Austria, Invited talk
2011 Elected Member of the Science Program for Excellence in Science, American Association for the Advancement of Science (AAAS)
2011 BioVision.Nxt fellow, BioVision, 7th World Life Sciences Forum, Lyon, France
2008 Novartis European Biotechnology Leadership Camp, Basel, Switzerland, Selected participant
2005 Chairman of the French Charter of the Young European Biotech Network (YEBN)
- Structural basis for AcrVA4 inhibition of specific CRISPR-Cas12a. GJ Knott, BF Cress, JJ Liu, BW Thornton, RJ Lew, B Al-Shayeb, .... eLife 8, e49110 2019.
- Circularly permuted and PAM-modified Cas9 variants broaden the targeting scope of base editors. TP Huang, KT Zhao, SM Miller, NM Gaudelli, BL Oakes, C Fellmann, .... Nature biotechnology 37 (6), 626 2019.
- Controlling CRISPR-Cas9 with ligand-activated and ligand-deactivated sgRNAs. K Kundert, JE Lucas, KE Watters, C Fellmann, AH Ng, BM Heineike, .... Nature Communications 10 (1), 2127 2019.
- MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival. CS Lee, LC Lee, TL Yuan, S Chakka, C Fellmann, SW Lowe, NJ Caplen, .... Proceedings of the National Academy of Sciences 116 (10), 4508-4517 2019.
- CRISPR-Cas9 Circular Permutants as Programmable Scaffolds for Genome Modification. BL Oakes, C Fellmann, H Rishi, KL Taylor, SM Ren, DC Nadler, R Yokoo, .... Cell 176 (1-2), 254-267. e16 2019.
- Systematic discovery of natural CRISPR-Cas12a inhibitors. KE Watters, C Fellmann, HB Bai, SM Ren, JA Doudna. Science 362 (6411), 236-239 2018.
- Disruption of the β1L isoform of GABP reverses glioblastoma replicative immortality in a TERT promoter mutation-dependent manner. A Mancini, A Xavier-Magalhães, WS Woods, KT Nguyen, AM Amen, .... Cancer Cell 34 (3), 513-528. e8 2018.
- Extension of the crRNA enhances Cpf1 gene editing in vitro and in vivo. HM Park, H Liu, J Wu, A Chong, V Mackley, C Fellmann, A Rao, F Jiang, .... Nature Communications 9 (1), 3313 2018.
- Differential Effector Engagement by Oncogenic KRAS. TL Yuan, A Amzallag, R Bagni, M Yi, S Afghani, W Burgan, N Fer, .... Cell Reports 22 (7), 1889-1902 2018.
- Prediction of potent shRNAs with a sequential classification algorithm. R Pelossof, L Fairchild, CH Huang, C Widmer, VT Sreedharan, N Sinha, .... Nature Biotechnology 35 (4), 350-353 2017.
- Cornerstones of CRISPR-Cas in drug discovery and therapy. C Fellmann, BG Gowen, PC Lin, JA Doudna, JE Corn. Nature Reviews Drug Discovery 16 (2), 89-100 2017.
- Profiling of engineering hotspots identifies an allosteric CRISPR-Cas9 switch. BL Oakes, DC Nadler, A Flamholz, C Fellmann, BT Staahl, JA Doudna, .... Nature biotechnology 34 (6), 646-651 2016.
- MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2. DG Nowak, H Cho, T Herzka, K Watrud, DV DeMarco, VMY Wang, .... Cancer discovery 5 (6), 636-651 2015.
- MODIFIED MIRNA AS A SCAFFOLD FOR SHRNA. C Fellmann. US Patent 20,150,018,539 2015.
- A Computational Algorithm to Predict shRNA Potency. SRV Knott, AR Maceli, N Erard, K Chang, K Marran, X Zhou, A Gordon, .... Molecular cell 56 (6), 796-807 2014.
- High throughput methods for functionally determining RNA interference efficiency. C Fellmann, SW Lowe, GJ Hannon, JE Zuber. US Patent 8,901,288 2014.
- Development of siRNA payloads to target KRAS-mutant cancer. TL Yuan, C Fellmann, CS Lee, CD Ritchie, V Thapar, LC Lee, DJ Hsu, .... Cancer discovery 4 (10), 1182-1197 2014.
- Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma. F Robert, W Roman, A Bramoullé, C Fellmann, A Roulston, C Shustik, .... Proceedings of the National Academy of Sciences 111 (37), 13421-13426 2014.
- Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. P Lito, A Saborowski, J Yue, M Solomon, E Joseph, S Gadal, .... Cancer Cell 25 (5), 697-710 2014.
- Stable RNA interference rules for silencing. C Fellmann, SW Lowe. Nature cell biology 16 (1), 10-18 2014.
- An optimized microRNA backbone for effective single-copy RNAi. C Fellmann, T Hoffmann, V Sridhar, B Hopfgartner, M Muhar, M Roth, .... Cell reports 5 (6), 1704-1713 2013.
- A pipeline for the generation of shRNA transgenic mice. LE Dow, PK Premsrirut, J Zuber, C Fellmann, K McJunkin, C Miething, .... Nature protocols 7 (2), 374-393 2012.
- Tiling genomes of pathogenic viruses identifies potent antiviral shRNAs and reveals a role for secondary structure in shRNA efficacy. X Tan, ZJ Lu, G Gao, Q Xu, L Hu, C Fellmann, MZ Li, H Qu, SW Lowe, .... Proceedings of the National Academy of Sciences 109 (3), 869-874 2012.
- An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. J Zuber, AR Rappaport, W Luo, E Wang, C Chen, AV Vaseva, J Shi, .... Genes & development 25 (15), 1628-1640 2011.
- Functional identification of optimized RNAi triggers using a massively parallel sensor assay. C Fellmann, J Zuber, K McJunkin, K Chang, CD Malone, RA Dickins, Q Xu, .... Molecular cell 41 (6), 733-746 2011.
- Toolkit for evaluating genes required for proliferation and survival using tetracycline-regulated RNAi. J Zuber, K McJunkin, C Fellmann, LE Dow, MJ Taylor, GJ Hannon, .... Nature biotechnology 29 (1), 79-83 2011.
- HIF-1 antagonizes p53-mediated apoptosis through a secreted neuronal tyrosinase. A Sendoel, I Kohler, C Fellmann, SW Lowe, MO Hengartner. Nature 465 (7298), 577-583 2010.