Moritz Jakab

All Publications

• Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency. Nature cancer Jakab, M., Lee, K. H., Uvarovskii, A., Ovchinnikova, S., Kulkarni, S. R., Jakab, S., Rostalski, T., Spegg, C., Anders, S., Augustin, H. G. 2024

  Abstract

  In metastasis, cancer cells travel around the circulation to colonize distant sites. Due to the rarity of these events, the immediate fates of metastasizing tumor cells (mTCs) are poorly understood while the role of the endothelium as a dissemination interface remains elusive. Using a newly developed combinatorial mTC enrichment approach, we provide a transcriptional blueprint of the early colonization process. Following their arrest at the metastatic site, mTCs were found to either proliferate intravascularly or extravasate, thereby establishing metastatic latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing mTCs to follow the extravasation-latency route. Surprisingly, mTC responsiveness towards niche-derived Wnt was established at the epigenetic level, which predetermined tumor cell behavior. Whereas hypomethylation enabled high Wnt activity leading to metastatic latency, methylated mTCs exhibited low activity and proliferated intravascularly. Collectively the data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche.

  View details for DOI 10.1038/s43018-023-00716-7

  View details for PubMedID 38308117

• Identification of hypertrophy-modulating Cullin-RING ubiquitin ligases in primary cardiomyocytes FRONTIERS IN PHYSIOLOGY Fischer, M., Jakab, M., Hirt, M. N., Werner, T. R., Engelhardt, S., Sarikas, A. 2023; 14: 1134339

  Abstract

  Cullin-RING ubiquitin ligases (CRL) regulate numerous biological processes in the heart and have been implicated in regulating cardiac hypertrophy. This study aimed to identify novel hypertrophy-modulating CRLs in cardiomyocytes (CM). A functional genomic approach using siRNA-mediated depletion and automated microscopy was employed to screen for cell size-modulating CRLs in neonatal rat CM. Screening hits were confirmed by 3H-isoleucine incorporation. Of 43 targets screened, siRNA-mediated depletion of Fbxo6, Fbxo45, and Fbxl14 resulted in decreased cell size, whereas depletion of Fbxo9, Fbxo25, Fbxo30, Fbxo32, Fbxo33, Cullin1, Roc1, Ddb1, Fbxw4, and Fbxw5 led to a markedly increased cell size under basal conditions. In CM stimulated with phenylephrine (PE), depletion of Fbxo6, Fbxo25, Fbxo33, Fbxo45, and Fbxw4 further augmented PE-induced hypertrophy. As a proof-of-concept, the CRLFbox25 was analysed by transverse aortic constriction (TAC) resulting in a 4.5-fold increase in Fbxo25 protein concentrations compared to control animals. In cell culture, siRNA-mediated depletion of Fbxo25 resulted in a ∼ 37% increase in CM cell size and ∼41% increase in 3H-isoleucine incorporation. Depleting Fbxo25 resulted in upregulation of Anp and Bnp. In summary, we identified 13 novel CRLs as positive or negative regulators of CM hypertrophy. Of these, CRLFbox25 was further characterized, as a potential modulator of cardiac hypertrophy.

  View details for DOI 10.3389/fphys.2023.1134339

  View details for Web of Science ID 000956987400001

  View details for PubMedID 36969608

  View details for PubMedCentralID PMC10030680

• A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie-Wnt signaling axis in the liver DEVELOPMENTAL CELL Inverso, D., Shi, J., Lee, K., Jakab, M., Ben-Moshe, S., Kulkarni, S. R., Schneider, M., Wang, G., Komeili, M., Velez, P., Riedel, M., Spegg, C., Ruppert, T., Schaeffer-Reiss, C., Helm, D., Singh, I., Boutros, M., Chintharlapalli, S., Heikenwalder, M., Itzkovitz, S., Augustin, H. G. 2021; 56 (11): 1677-+

  Abstract

  Single-cell transcriptomics (scRNA-seq) has revolutionized the understanding of the spatial architecture of tissue structure and function. Advancing the "transcript-centric" view of scRNA-seq analyses is presently restricted by the limited resolution of proteomics and genome-wide techniques to analyze post-translational modifications. Here, by combining spatial cell sorting with transcriptomics and quantitative proteomics/phosphoproteomics, we established the spatially resolved proteome landscape of the liver endothelium, yielding deep mechanistic insight into zonated vascular signaling mechanisms. Phosphorylation of receptor tyrosine kinases was detected preferentially in the central vein area, resulting in an atypical enrichment of tyrosine phosphorylation. Prototypic biological validation identified Tie receptor signaling as a selective and specific regulator of vascular Wnt activity orchestrating angiocrine signaling, thereby controlling hepatocyte function during liver regeneration. Taken together, the study has yielded fundamental insight into the spatial organization of liver endothelial cell signaling. Spatial sorting may be employed as a universally adaptable strategy for multiomic analyses of scRNA-seq-defined cellular (sub)-populations.

  View details for DOI 10.1016/j.devcel.2021.05.001

  View details for Web of Science ID 000659463100012

  View details for PubMedID 34038707

  View details for PubMedCentralID PMC8191494