Moritz Jakab

All Publications

• NSD2 inhibitors rewire chromatin to treat lung and pancreatic cancers. Nature Jeong, J., Hausmann, S., Dong, H., Szczepski, K., Flores, N. M., Garcia Gonzalez, A., Shi, L., Lu, X., Lempiäinen, J., Jakab, M., Zeng, L., Chasan, T., Bareke, E., Dong, R., Carlson, E., Padilla, R., Husmann, D., Thompson, J., Shipman, G. A., Zahn, E., Barnes, C. A., Khan, L. F., Albertorio-Sáez, L. M., Brill, E., Kumary, V. U., Marunde, M. R., Maryanski, D. N., Szany, C. C., Venters, B. J., Windham, C. L., Nowakowski, M. E., Czaban, I., Jaremko, M., Keogh, M. C., Le, K., Soth, M. J., Garcia, B. A., Jaremko, Ł., Majewski, J., Mazur, P. K., Gozani, O. 2025

  Abstract

  NSD2 catalyses the epigenetic modification H3K36me2 (refs. 1,2) and is a candidate convergent downstream effector of oncogenic signalling in diverse malignancies3-5. However, it remains unclear whether the enzymatic activity of NSD2 is therapeutically targetable. Here we characterize a series of clinical-grade small-molecule catalytic NSD2 inhibitors (NSD2i) and show that the pharmacological targeting of NSD2 constitutes an epigenetic dependency with broad therapeutic efficacy in KRAS-driven preclinical cancer models. NSD2i inhibits NSD2 with single-digit nanomolar half-maximal inhibitory concentration potency and high selectivity over related methyltransferases. Structural analyses reveal that the specificity of NSD2i for NSD2 is due to competitive binding with S-adenosylmethionine and catalytic disruption through a binary-channel obstruction mechanism. Proteo-epigenomic and single-cell strategies in pancreatic and lung cancer models support a mechanism in which sustained NSD2i exposure reverses pathological H3K36me2-driven chromatin plasticity, re-establishing silencing at H3K27me3-legacy loci to curtail oncogenic gene expression programs. Accordingly, NSD2i impairs the viability of pancreatic and lung cancer cells and the growth of patient-derived xenograft tumours. Furthermore, NSD2i, which is well-tolerated in vivo, prolongs survival in advanced-stage autochthonous KRASG12C-driven pancreatic and lung tumours in mouse models to a comparable level as KRAS inhibition with sotorasib6. In these models, treatment with both a NSD2 inhibitor and sotorasib synergize to confer sustained survival with extensive tumour regression and elimination. Together, our work uncovers targeting of the NSD2-H3K36me2 axis as an actionable vulnerability in difficult to treat cancers and provides support for the evaluation of NSD2 and KRAS inhibitor combination therapies in a clinical setting.

  View details for DOI 10.1038/s41586-025-09299-y

  View details for PubMedID 40770093

  View details for PubMedCentralID 2797197

• 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. N., Werner, T. R. 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

• Tie2 Receptor in Tumor-Infiltrating Macrophages Is Dispensable for Tumor Angiogenesis and Tumor Relapse after Chemotherapy CANCER RESEARCH Jakab, M., Rostalski, T., Lee, K., Mogler, C., Augustin, H. G. 2022; 82 (7): 1353-1364

  Abstract

  Tumor relapse after chemotherapy relies on the reconstruction of damaged tumor vasculature. In this context, proangiogenic Tie2-expressing macrophages have been suggested to serve as crucial instructors of tumor revascularization by secreting angiogenic factors while being closely associated with the vessel wall. Although the proangiogenic nature of Tie2+ macrophages is well described, the functional contribution of macrophage Tie2 expression remains elusive. Here, we employed a Cre-loxP system to specifically delete Tie2 in macrophages. In multiple syngeneic solid tumor models and two distinct chemotherapeutic treatment regimens, macrophage-expressed Tie2 did not contribute to primary tumor growth, tumor revascularization after chemotherapy, tumor recurrence, or metastasis. Exposing cultured murine macrophage cell lines and bone marrow-derived macrophages to hypoxia or stimulating them with Ang2 did not induce expression of Tie2 at the RNA or protein level. Furthermore, a comprehensive meta-analysis of publicly available single cell RNA sequencing datasets of human and murine tumor-infiltrating CD11b+ myeloid cells did not reveal a transcriptionally distinct macrophage population marked by the expression of Tie2. Collectively, these data question the previously reported critical role of Tie2-expressing macrophages for tumor angiogenesis and tumor relapse after chemotherapy. Moreover, lack of Tie2 inducibility and absence of Tie2-positive macrophages in multiple recently published tumor studies refute a possible prognostic value of macrophage-expressed Tie2.Multiple preclinical tumor models, cell stimulation experiments, and meta-analysis of published tumor single cell RNA sequencing data challenge the reported role of Tie2-positive macrophages for tumor angiogenesis, metastasis, and relapse after chemotherapy. See related commentary by Zhang and Brekken, p. 1172.

  View details for DOI 10.1158/0008-5472.CAN-21-3181

  View details for Web of Science ID 000782752000001

  View details for PubMedID 35373291

  View details for PubMedCentralID PMC9762345

• 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

• Understanding angiodiversity: insights from single cell biology DEVELOPMENT Jakab, M., Augustin, H. G. 2020; 147 (15)

  Abstract

  Blood vessels have long been considered as passive conduits for delivering blood. However, in recent years, cells of the vessel wall (endothelial cells, smooth muscle cells and pericytes) have emerged as active, highly dynamic components that orchestrate crosstalk between the circulation and organs. Encompassing the whole body and being specialized to the needs of distinct organs, it is not surprising that vessel lining cells come in different flavours. There is calibre-specific specialization (arteries, arterioles, capillaries, venules, veins), but also organ-specific heterogeneity in different microvascular beds (continuous, discontinuous, sinusoidal). Recent technical advances in the field of single cell biology have enabled the profiling of thousands of single cells and, hence, have allowed for the molecular dissection of such angiodiversity, yielding a hitherto unparalleled level of spatial and functional resolution. Here, we review how these approaches have contributed to our understanding of angiodiversity.

  View details for DOI 10.1242/dev.146621

  View details for Web of Science ID 000576686400001

  View details for PubMedID 32792338