Kathleen Klotz-Noack's research while affiliated with Charité Universitätsmedizin Berlin and other places

Publications (9)

Article
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In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue lacking visible organization. We sought to define transcriptional states of colorectal cancer cells and signals controlling their development by performing single-cell transcriptome analysis of tumors and matched non...
Article
In colorectal cancer (CRC), the prevalence of NRAS mutations (5–9%) is inferior to that of KRAS mutations (40–50%). NRAS mutations feature lately during tumour progression and drive resistance to anti-EGFR therapy in KRAS wild-type tumours. To elucidate specific functions of NRAS mutations in CRC, we expressed doxycycline-inducible G12D and Q61K mu...
Article
Full-text available
Oncoproteins such as the BRAFV600E kinase endow cancer cells with malignant properties, but they also create unique vulnerabilities. Targeting of BRAFV600E-driven cytoplasmic signaling networks has proved ineffective, as patients regularly relapse with reactivation of the targeted pathways. We identify the nuclear protein SFPQ to be synthetically l...
Article
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To unravel vulnerabilities of KRAS-mutant CRC cells, a shRNA-based screen specifically inhibiting MAPK pathway components and targets was performed in CaCo2 cells harboring conditional oncogenic KRASG12V. The custom-designed shRNA library comprised 121 selected genes, which were previously identified to be strongly regulated in response to MEK inhi...
Article
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We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at...
Article
Although histone deacetylase inhibitors (HDACi) are considered a promising novel therapeutic approach in the light of their potent tumour-selective effects, the use of these inhibitors for treatment of colorectal cancer (CRC) have thus far demonstrated limited success as a monotherapy. What this eventually boils down to is our incomplete understand...
Article
Full-text available
To prevent re-replication of DNA in a single cell cycle, the licensing of replication origins by Mcm2-7 is prevented during S and G2 phases. Animal cells achieve this by cell-cycle-regulated proteolysis of the essential licensing factor Cdt1 and inhibition of Cdt1 by geminin. Here we investigate the consequences of ablating geminin in synchronised...
Article
In this issue of Molecular Cell, Kawabata et al. (2011) show that mice hypomorphic for the replication licensing protein Mcm4 show spontaneous DNA replication defects due to a lack of dormant origins, potentially explaining why these mice are cancer prone.

Citations

... Thus such finding can contribute to better treatment design [157]. Likewise, single cell analysis of normal colon and CRC tissue reveled WNT-independent MAPK activity in CRC as a key driver of tumor cell plasticity [158]. Furthermore, as CRC display a high degree of tumor heterogeneity, recent single-cell RNA sequencing analysis revealed heterogeneity in gene regulatory networks and identified CRC critical regulators such as transcription factor ERG [159]. ...
... SFPQ has both DNA and RNAbinding domains involved in a variety of cellular activities, including RNA transport, cell cycle regulation, DNA damage and repair, and apoptosis control. Several studies have reported that SFPQ can increase the growth, metastasis, and chemoresistance of cancer cells such as liver cancer, breast cancer, ovarian cancer, and colorectal cancers, although the precise mechanism by which SFPQ promotes cancer malignant phenotypes remains unknown (21)(22)(23)(24)(25)(26). ...
... Additionally, normal cells respond to licensing inhibitors by activating a licensing checkpoint and arresting temporarily in G1 phase (Matson et al., 2019;Mcintosh and Blow, 2012). On the contrary, the genetically unstable cancer cells might possibly have a defective licensing checkpoint (Shreeram et al., 2002;Nevis et al., 2009;Zimmerman et al., 2013;Gastl et al., 2020) while ectopic licensing of origins of replication outside G1 phase can cause genome re-replication (Klotz-Noack et al., 2012;Muñoz et al., 2017). A similar mechanism of action has been suggested for a family of arylquinolin-amines that was identified as inhibitors of replication licensing, by preventing the tight ORC-DNA interaction required for MCM2-7 loading onto chromatin (Gardner et al., 2017). ...
... Those characteristics included high expression of MDR1; high capacities for proliferation, colony formation, and invasion; and in vivo generation of tumors overexpressing the proliferation-associated markers Ki67, c-MYC, and pERK. Those properties were absent in the non-SP fraction (Fig. 5B, C). pERK plays critical roles in cell cycle progression via c-MYC stabilization, EMT via ZEB1 induction, apoptosis, autocrine cytokine loops, cancer metabolism, and protein translation [35,36]. Consistently, pERK may drive c-MYC and Ki67 expression, resulting in the formation of larger tumors from HHUA-SP cells than from non-SP HHUA cells (Fig. 5B, C ). ...
... Indeed, by applying sensitized emission FRET in MCF7 cancer cells we could demonstrate the inhibitory effect of compound AF615 on Geminin-CDT1. Origin relicensing accompanied by CDT1 overexpression or Geminin down-regulation, induces DNA re-replication in different cancer cell lines, promoting the activation of the DNA damage response, inhibition of DNA synthesis and cell cycle arrest in S or G2 phase (Klotz-Noack et al., 2012;Muñoz et al., 2017;Zhou et al., 2020). By employing high content imaging and automated image analysis, we identified activation of the DNA damage response in different cancer cell lines treated with compound AF615. ...
... Curiously, multiple Mcm2-7 complexes can be loaded in vitro and during initiation in cells, even though only two are destined to become part of an active replication fork (209,210). This so-called MCM paradox (211) differs from bacterial initiation, in which only two molecules of DnaB are deposited per round of origin firing (145,212) and may have a role in helping to overcome replication fork stalling, for example, by the activation of dormant origins (212). ...