Biology subjects

Soucek, L.

Publications and source records attributed to Soucek, L..

4 recordsLinked to original sources

bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗

bioRxiv2025

A CDCA2 - MYC positive feedback loop controls cancer cells survival

MYC transcription factors are encoded by a small family of genes which include, in addition to the prototype member MYC, MYCN and MYCL. The majority of human cancers display expression alterations of MYC genes and their products, making this group of oncoproteins among the most relevant therapeutic targets in oncology. MYC is regulated at multiple levels, and protein phosphorylation is a critical mechanism used by the cell to modulate MYC stability and activity. Although there is a reasonable knowledge of the kinases required for MYC modifications, the counteracting phosphatases have been relatively understudied. Here we have investigated the role of the chromatin remodelling factor and protein phosphatase 1 (PP1) regulatory subunit CDCA2, also known as RepoMan, in the regulation of MYC proteins in cancer cells. Using RNA interference and regulatable degron-mediated degradation of CDCA2, we demonstrate that the PP1 subunit is required for MYC and MYCN stabilisation and viability of triple negative breast cancer, neuroblastoma and colon cancer cells. Proximity ligation assays indicate that both MYC and MYCN are in close proximity of CDCA2 in vivo. Furthermore, chromatin immunoprecipitation data and promoter mutation studies establish that CDC2A is a bone-fide MYC target gene in cancer cells, revealing a reciprocal regulatory loop that could be exploited for therapeutic purposes.

cell biology↗

bioRxiv2020

Integrated requirement of non-specific and sequence-specific DNA binding in MYC-driven transcription

Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity: how these binding modes are integrated to determine select transcriptional outputs remains unresolved. We designed mutants of the MYC transcription factor bearing substitutions in residues that contact either the DNA backbone or specific bases within the consensus binding motif (E-box), and profiled their DNA-binding and gene-regulatory activities in murine cells. Our data reveal that non-specific DNA binding is required for MYC to engage onto active regulatory elements in the genome, preceding sequence recognition; beyond merely stabilizing MYC onto select target loci, sequence-specific binding contributes to its precise positioning and - most unexpectedly - to transcriptional activation per se. In particular, at any given binding intensity, promoters targeted via the cognate DNA motif were more frequently activated by MYC. Hence, seemingly promiscuous chromatin interaction profiles actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.

molecular biology↗

bioRxiv2019

Myc instructs and maintains pancreatic adenocarcinoma phenotype

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its dismal prognosis and its signature fibroinflammatory phenotype. We show that activation of Myc in PanIN epithelial cells is alone sufficient to instruct and maintain immediate transition of indolent PanINs to PDACs phenotypically identical to the spontaneous human disease. Myc does this by inducing a distinct, tissue-specific ensemble of instructive signals that, together, coordinate changes in multiple, stromal and inflammatory cell types to generate the signature PDAC stroma. We also demonstrate that the Myc PDAC switch is completely reversible and that Myc deactivation immediately triggers meticulous disassembly of both PDAC tumor and stroma. Hence, both the formation and deconstruction of the complex PDAC phenotype may be mediated by a single, reversible molecular switch. SIGNIFICANCEPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and lacks effective therapies. We show that Myc is a single molecular switch that directly and immediately instructs transition from indolent KRasG12D-induced PanIN to the characteristic complex, multi-cell-type fibroinflammatory and immune-cold PDAC phenotype through the release of a distinct, tissuespecific set of instructive signals. The same combination of KRasG12D and Myc drives a very different phenotype in lung, indicating that the principal phenotypes of adenocarcinomas are dictated by tissue of origin not specific oncogenes. We also show that the Myc switch is immediately and completely reversible: blocking Myc function triggers meticulous disassembly of the entire PDAC tumor-stromal edifice demonstrating that phenotypic complexity is not a barrier to effective treatment of cancers.

cancer biology↗