Biology subjects

Suetterlin, M.

Publications and source records attributed to Suetterlin, M..

4 recordsLinked to original sources

bioRxiv2025

Interplay between BET Proteins and the Pre-Replication Complex Unveils Therapeutic Vulnerabilities in Cancer

Replication stress is a critical event in cancer development and understanding the underlying molecular mechanisms can help to identify new treatment strategies. Here, we investigate the molecular interplay between the pre-replication complex (pre-RC) and the bromodomain and extraterminal domain (BET) proteins in orchestrating replication stress response. Our findings reveal a mutual dependency between BET proteins and the pre-RC within cancer cells. Notably, reduction in origin licensing or replication initiation makes cells more susceptible to the BET-inhibitor AZD5153. Furthermore, we observe synergistic effects when combining the CDC7 inhibitor XL413 with AZD5153, effects which were partly dependent on TP53 mutation status. This combination treatment results in unresolved DNA damage and R-loop formation, leading to increased genomic instability. These insights pave the way for novel strategies for targeted cancer therapies and provide a foundation for further investigation into the interplay between CDC7 and BET proteins in replication stress response. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/645172v2_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@f5b170org.highwire.dtl.DTLVardef@545fbeorg.highwire.dtl.DTLVardef@159b631org.highwire.dtl.DTLVardef@c851cf_HPS_FORMAT_FIGEXP M_FIG C_FIG The graphic illustrates how the CDC7 inhibitor XL413 and the BET inhibitor AZD5153 work together in TP53-deficient cancer cells. First, XL413 prevents activation of the origin of replication complex, leading to DNA damage. Second, the DNA repair machinery is unable to resolve this damage, resulting in the accumulation of unresolved R-loops and genomic instability. Ultimately, this cascade culminates in cell death.

cancer biology↗

bioRxiv2023

Inhibition of Replication Origins and ATR Synergistically Activates the Innate Immune System in Cancer Cells

Sufficient numbers of activated replication origins are essential for successful DNA replication. While normal cells load replication origins in abundance to the genome, cancer cells often load fewer origins of replication due to genomic alterations such as CCNE1 amplifications. Here we exploit this feature to sensitize cancer cells to ATR inhibition. We show by using siRNA and small molecules that the inhibition of origin activation as well as the reduction of replication origins itself sensitizes ovarian cancer cell lines against ATR inhibition by inducing genomic instability. We further show that in ovarian cancer cells this combinatorial approach leads to an increased genomic instability which manifests in an increase of micronuclei that consequently activate the innate immune system through the cGAS-STING pathway. Notably, no activation of the innate immune system was observed in immortalized fallopian tube cells. However, overexpression of Cyclin E1 in this model leads to a marked increase in genomic instability and innate immune activation. Here we provide preclinical evidence to increase the therapeutic efficacy of ATR inhibitors. Additionally, this approach could help to activate innate immunity and increase T-cell immune infiltration in tumors, providing a rationale for a combination with immune checkpoint inhibitors.

cancer biology↗

bioRxiv2020

Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer

Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.

cancer biology↗

bioRxiv2017

Resolving Drug Effects In Patient-Derived Cancer Cells Links Organoid Responses To Genome Alterations

Cancer drug screening in patient-derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy-based assay to resolve drug-induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevant drugs. Drug-induced growth arrest and efficacy of cytostatic drugs differed between the two culture systems. Interestingly, drug effects in organoids were more diverse and had lower therapeutic potential. Genomic analysis revealed novel links between drug sensitivity and DNA repair deficiency in organoids that were undetectable in monolayers. Thus, our results highlight the dependency of cytostatic drugs and pharmacogenomic associations on culture systems, and guide culture selection for drug tests.

cancer biology↗