Biology subjects

Teles, J.

Publications and source records attributed to Teles, J..

2 recordsLinked to original sources

bioRxiv2026

WNT-driven chromosomal instability as a biomarker for PORCN inhibition

Targeting Porcupine (PORCN), a key regulator of the WNT-signalling pathway, has shown therapeutic potential in multiple cancers. Despite strong target engagement and acceptable safety profiles through human phase I clinical trials, low phase II efficacy has stalled further clinical development. Given that aberrant WNT signalling can drive tumorigenesis by inducing chromosomal instability (CIN), we hypothesised that genomic CIN signatures might serve as a predictive biomarker to help improve response rates. Using a controlled in vitro model and single-cell whole-genome sequencing, we demonstrate that acute WNT-activation directly induces three distinct types of CIN: whole genome duplication, replication stress, and impaired homologous recombination. We translated these observations into a composite CIN signature biomarker that significantly correlated with both genetic dependency and pharmacological inhibition of PORCN across 195 and 24 cell lines, respectively. Through a large-scale meta-analysis of patient-derived and cell line xenografts, we established that this composite CIN signature biomarker quantitatively predicts in vivo PORCN inhibitor sensitivity (R=-0.71, p<0.002). By applying an optimised biomarker threshold, refined through modelling of human patient data, to the The Cancer Genome Atlas dataset, we successfully retrospectively modelled previous trial results and identified gastroesophageal cancers as a high-prevalence (36.6%) indication for future development. We validated this strategy in a mouse clinical trial of gastric and esophageal xenografts, where biomarker-guided stratification achieved an objective response rate of 60% and significantly decreased risk of progression (HR=0.21, p=0.0345). These data establish an actionable, trail-ready framework for further PORCN inhibitor clinical development.

cancer biology↗

bioRxiv2017

Revisiting the erythroid-myeloid lineage decision - a data-driven dynamical model analysis

It is widely conjectured that the mutually antagonizing pair of transcription factors GATA1 and PU.1, deter-mines the choice between the erythroid and myeloid lineages in hematopoiesis. In theoretical approaches, this appears natural with a bistable switch driving the decision. Recent extensive binding and gene expression experiments with some focus on the triad GATA1, GATA2 and PU.1 indicate that GATA2 may be more involved in this lineage decision than previously anticipated. Here, we analyze these experimental data by modeling regulatory sub-networks with deterministic rate equations. Using network dynamical parameters determined by the data, we deduce from increasing the self-interaction bindings in silico among the triad genes that GATA2 and PU.1 exhibit non-linear behavior with one unstable and one stable state. This is in contrast to GATA1, which shows smoother behavior. We extend the network to include the downstream regulators FOG1 and CEBPA, and extract the nature of the corresponding regulatory interactions, excitatory or suppressing, between this pair and the triad by fitting to experimental gene expression time series. Based on this extended network, we simulate and explore different knockout scenarios, providing insight into the role of these regulators in the process of lineage specification, as well as predictions for future experimental validation. We address the mechanism of GATA switching as a mechanism of lineage differentiation by investigating the dynamics of FOG1 regulation by GATA2 and GATA1. Overall, this analysis strongly suggests that within this network, GATA2 is the key driver of erythroid lineage specification through its repression of PU.1, whereas GATA1 appears to be more relevant for the downstream differentiation events.

systems biology↗