Our Research

The Teleman Lab is interested in understanding cell and tissue growth. Compared to the cell cycle, the mechanisms controlling cell growth and tissue growth are less well understood. We study two aspects of cell growth: metabolism and signaling:

• Metabolism: To grow, cells and tissues need to make biosynthetic building blocks to accumulate mass. This requires the activation of metabolic pathways that support anabolism and fight oxidative stress.
• Signaling: Cell metabolism, in turn, is regulated by signaling pathways such as the insulin pathway or the mTORC1 pathway. These signaling pathways sense and respond to growth factors and nutrient levels. We investigate the regulation of these signaling processes controlling metabolism and energy consumption.

This research has implications for both basic biology and cancer biology:

• Basic biology: Tissue growth and size control represents one of the unsolved fundamental mysteries in developmental biology. How does a tissue know what size to become, and when to stop growing? How does a tissue measure its size? The underlying mechanisms are not known.
• Cancer biology: To form a tumor, cells need to both proliferate and grow. Understanding the molecular mechanism controlling cell growth, and the metabolic pathways that generate biomass, is an important part of understanding cancer.

Since tissue growth control is a conserved process in all animals, we use both Drosophila and human cells in culture as model systems. We use Drosophila mainly for gene discovery and for organismal studies. We use mammalian cell culture to study basic biological mechanisms, to screen for genes involved in processes of interest, and to translate our findings from flies into mammals. We also study patient samples with our collaborators at the Heidelberg University Hospital.

Finding a therapy for Neurofibromatosis Type II

Neurofibromatosis Type II (NFII) is a genetic condition characterized by predisposition to benign tumors of the peripheral nervous system. It is caused by homozygous loss-of-function of the homonymous gene NF2 in Schwann cells, the glia that ensheath peripheral nerves. Individuals with NFII typically harbor a germline mutation in one of the two NF2 alleles. Recurrent, stochastic, somatic loss of the second NF2 allele gives rise to tumors throughout the lifetime of the patients. These tumors grow and constrict the nerves. Since cranial nerves are often affected, this leads to balance problems, dizziness, headaches, facial weakness, and loss of hearing or sight. Unfortunately, there is no approved pharmacological therapy for NFII. Tumors are surgically resected, leading to nerve damage. Since patients recurrently develop new tumors, they need to return to the hospital for tumor resections every few years, leading to significant morbidity.

We are working on developing a pharmacological therapy for NFII. To this end, we performed a screen to search for genes that, when knocked-down or inhibited, cause death of NF2 mutant Schwann cells (ie the tumor) but not of NF2 wildtype or NF2 heterozygous Schwann cells (ie the rest of the patient). This identified a target, the metabolic enzyme G6PD. Inhibition of G6PD induces death of NF2 knockout but not NF2 wildtype Schwann cells (see figure to the right). This means that if we develop a drug that inhibits G6PD, we should be able to kill NF2 mutant tumors. Indeed, in work done together with the DKFZ xenograft core facility, we found that G6PD inhibition kills NF2 mutant xenografts in mice.

We are now developing a drug targeting G6PD together with Evotec and Bristol Myers Squibb in a beLAB2122 project.

Reference: Kyrkou A, Valla R, Zhang Y, Ambrosi G, Laier S, Müller-Decker K, Boutros M and Teleman AA. G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells. (2024) Nature Communications 5:5115 [pubmed]

Discovering new genes that cause Schwannomas

As a side-product of the screen we did for genes regulating Schwann cells proliferation and survival, we also discovered several new genes that act as tumor suppressors in Schwann cells. We are now working on them to characterize their phenotype, to understand their molecular mode of action, and to understand whether they are mutated in human Schwannomas. We hope this work will uncover genes that are responsible for the initiation of Schwannomas, improving our understanding of this disease, and identifying new approaches for targeting the disease.

Understanding growth control during development

A fundamental question in developmental biology is to understand how organs can measure and regulate their size. For instance, the two legs of a person or the two wings of a fly are usually identical in size to within 1%. How this is controlled at the molecular level is a mystery.

During animal development tissues increase tremendously in mass, growing roughly 1000-fold from the embryo to the adult. Each tissue then stops at a very precise size, which is determined by a combination of genetic and environmental factors. We aim to unravel the molecular machinery controlling this termination of growth. We believe this is relevant for cancer biology, where tumors do not respect the regulation of correct organ size.

The best studied model system for growth control is the fly wing due to the extensive genetic tools available to manipulate gene expression in time and space. We use this system to study how signaling pathways control growth, such as the 

(1) Insulin / PI3K / mTOR, 
(2) Hippo / Yorkie/YAP, and 
(3) Dpp (TGF-beta) pathways.

References:

• Willnow P and Teleman AA. Nuclear position and local acetyl-CoA production regulate chromatin state. (2024) Nature 630:466-474 [pubmed]
• Strassburger K, Lutz M, Müller S and Teleman AA. Ecdysone regulates Drosophila wing disc size via a TORC1 dependent mechanism. (2021) Nature Communications. 12(1):6684 [pubmed]
• Romero-Pozuelo J, Demetriades C, Schroeder P and Teleman AA. CycD/Cdk4 and discontinuities in Dpp signaling activate TORC1 in the Drosophila wing disc. (2017) Developmental Cell 42:376-87 [pubmed]
• Doumpas N, Ruiz-Romero M, Blanco E, Edgar B, Corominas M and Teleman AA. Brinker regulates wing disc growth in part via repression of Myc expression. (2013) EMBO Reports. 14:261-8 [pubmed]
• Teleman AA, Cohen SM, Dpp gradient formation in the Drosophila wing imaginal disc. (2000) Cell. 2000 Dec 8;103(6):971-80 [pubmed]

 

Cancer and non-canonical mRNA translation

To grow, cancer cells need to synthesize proteins. Cancer cells, however, face a challenge. Canonical “textbook” cap-dependent translation is turned off in response to cellular stresses. Hypoxia, nutrient limitation, ER stress, genotoxic stress and cytotoxic stress all inhibit canonical translation (by phosphorylating eIF2alpha and by inhibiting mTORC1, which leads to 4E-BP activation and eIF4E inhibition). Since almost all cancer cells have one stress or the other, they need to either bypass these inhibitory mechanisms, or to rely on alternate non-canonical translation mechanisms. We are studying some of these non-canonical translation mechanisms.

For instance, we discovered that the oncogenes DENR and MCTS1 promote a process called translation re-initiation, to promote expression of genes required for proliferation. Several projects in the lab focus on how translation is regulated, and how its dysregulation contributes to cancer.

Selected references

• Ahmed YL, Schleich S, Bohlen J, Mandel N, Simon B, Sinning I, Teleman AA. DENR-MCTS1 heterodimerization and tRNA recruitement are required for translation reinitiaion. (2018) PLoS Biology 16(6):e2005160. [pubmed]
• Bohlen J, Harbrecht L, Blanco S, Clemm von Hohenberg K, Fenzl K, Kramer G, Bukau B and Teleman AA. DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4. (2020) Nature Communications 11:4676. [pubmed]
• Bohlen J, Fenzl K, Kramer G, Bukau B and Teleman AA. Selective 40S footprinting reveals cap-tethered ribosome scanning in human cells. (2020) Molecular Cell 79:561-574.e5 [pubmed]
• Schleich S, Strassburger K, Janiesch PC, Koledachkina T, Miller KK, Haneke K, Cheng Y-C, Kuechler K, Stoecklin G, Duncan KE and Teleman AA. DENR•MCT-1 Promotes Translation Reinitiation Downstream of uORFs to Control Tissue Growth. (2014) Nature 512: 208-212 [pubmed]
• Schleich S, Acevedo JM, Clemm von Hohenberg K and Teleman AA. Identification of transcripts with short stuORFs as targets for DENR•MCTS1-dependent translation in human cells. (2017) Scientific Reports 7:3722 [pubmed]