Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer.

Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen-activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer-specific and overall survival.

In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer.

Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5-FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer.

Targeting tumor cell plasticity by combined inhibition of NOTCH and MAPK signaling in colon cancer.

In colorectal cancer, signaling pathways driving tumor progression are promising targets for systemic therapy. Besides WNT and MAPK signaling, activation of NOTCH signaling is found in most tumors. Here, we demonstrate that high NOTCH activity marks a distinct colon cancer cell subpopulation with low levels of WNT and MAPK activity and with a pronounced epithelial phenotype.

PBX3 Is Part of an EMT Regulatory Network and Indicates Poor Outcome in Colorectal Cancer.

Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial-mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer. We used transcriptomic and analyses to identify PBX3 expression in colorectal cancer and cell biology approaches to determine its regulation and function.

Multicolor lineage tracing reveals clonal architecture and dynamics in colon cancer.

Colon cancers are composed of phenotypically heterogeneous tumor cell subpopulations with variable expression of putative stem cell and differentiation antigens. While in normal colonic mucosa, clonal repopulation occurs along differentiation gradients from crypt base toward crypt apex, the clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. Using a multicolor lineage tracing approach in colon cancer xenografts that reflect primary colon cancer architecture, we here demonstrate that clonal outgrowth is mainly driven by tumor cells located at the leading tumor edge with clonal axis formation toward the tumor center.

Oncogenic Effects of High MAPK Activity in Colorectal Cancer Mark Progenitor Cells and Persist Irrespective of RAS Mutations.

About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling, which promotes tumor invasion and progression. Here, we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models, and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge, ceased to proliferate, underwent epithelial-mesenchymal transition (EMT), and expressed markers related to colon cancer stem cells.

ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer.

Constitutively active WNT signaling is a hallmark of colorectal cancers and a driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here, we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer.

CYB5R1 links epithelial-mesenchymal transition and poor prognosis in colorectal cancer.

Colorectal cancers show significant tumor cell heterogeneity within the same core genetic background. Epithelial-mesenchymal transition (EMT) is an important functional aspect of this heterogeneity and hallmark of colorectal cancer progression. Here, we identify CYB5R1, an enzyme involved in oxidative stress protection and drug metabolism, as an indicator of EMT in colon cancer.