PI3K/AKT signaling allows for MAPK/ERK pathway independency mediating dedifferentiation-driven treatment resistance in melanoma.

Background: Current therapeutic management of advanced melanoma patients largely depends on their BRAF mutation status. However, the vast heterogeneity of the tumors hampers the success of therapies targeting the MAPK/ERK pathway alone. Dissecting this heterogeneity will contribute to identifying key players in the oncogenic progression to tailor more effective therapies.

Dynamic transcriptome analysis reveals signatures of paradoxical effect of vemurafenib on human dermal fibroblasts.

Background: Vemurafenib (PLX4032) is one of the most frequently used treatments for late-stage melanoma patients with the BRAF mutation; however, acquired resistance to the drug poses as a major challenge. It remains to be determined whether off-target effects of vemurafenib on normal stroma components could reshape the tumor microenvironment in a way that contributes to cancer progression and drug resistance.

Methods: By using temporally-resolved RNA- and ATAC-seq, we studied the early molecular changes induced by vemurafenib in human dermal fibroblast (HDF), a main stromal component in melanoma and other tumors with high prevalence of BRAF mutations.

Identification and Validation of a Diagnostic and Prognostic Multi-Gene Biomarker Panel for Pancreatic Ductal Adenocarcinoma.

Late diagnosis and systemic dissemination essentially contribute to the invariably poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Therefore, the development of diagnostic biomarkers for PDAC are urgently needed to improve patient stratification and outcome in the clinic. By studying the transcriptomes of independent PDAC patient cohorts of tumor and non-tumor tissues, we identified 81 robustly regulated genes, through a novel, generally applicable meta-analysis.

Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation.

The nerve growth factor NGF has been shown to cause cell fate decisions toward either differentiation or proliferation depending on the relative activity of downstream pERK, pAKT, or pJNK signaling. However, how these protein signals are translated into and fed back from transcriptional activity to complete cellular differentiation over a time span of hours to days is still an open question. Comparing the time-resolved transcriptome response of NGF- or EGF-stimulated PC12 cells over 24 h in combination with protein and phenotype data we inferred a dynamic Boolean model capturing the temporal sequence of protein signaling, transcriptional response and subsequent autocrine feedback.

B-Raf inhibitors induce epithelial differentiation in BRAF-mutant colorectal cancer cells.

BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-Raf(V600E) oncoprotein.

Boolean approach to signalling pathway modelling in HGF-induced keratinocyte migration.

Motivation: Cell migration is a complex process that is controlled through the time-sequential feedback regulation of protein signalling and gene regulation. Based on prior knowledge and own experimental data, we developed a large-scale dynamic network describing the onset and maintenance of hepatocyte growth factor-induced migration of primary human keratinocytes. We applied Boolean logic to capture the qualitative behaviour as well as short-and long-term dynamics of the complex signalling network involved in this process, comprising protein signalling, gene regulation and autocrine feedback.