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Novel strategy to control STAT signalling axis

Signal transducers and activators of transcription (STATs) are latent, cytoplasmic transcription factors. Janus kinases (JAKs) and activated CDC42-associated kinase-1 (ACK1/TNK2) catalyse the phosphorylation of STAT1 and the expression of its target genes. Here we demonstrate that catalytically active ACK1 promotes the phosphorylation and nuclear accumulation of STAT1 in transformed kidney cells.

Nilotinib contributes to arterial occlusive disease in CML-patients

Chronic myeloid leukemia (CML) is increasingly treated with the BCR/ABL1 inhibitor Nilotinib. Although otherwise well-tolerated, Nilotinib has been associated with progressive arterial occlusive disease (AOD). Our objective was to determine the exact frequency of AOD and examine effects of Nilotinib and Imatinib on endothelial cells to explain AOD-development. In contrast to Imatinib, Nilotinib was found to upregulate pro-atherogenic adhesion-proteins (ICAM-1, E-selectin, VCAM-1) on human endothelial cells.

PAK2 promising target for leukemia

The p21-activated kinases (PAKs) are key nodes in oncogenic signalling pathways controlling growth, survival, and motility of cancer cells. Their activity is increased in many human cancers and is associated with poor prognosis. We show now that PAK1 and PAK2 are the critical isoforms in a BCR/ABL1+ haematopoietic malignancy. In suspension, leukaemic cells deficient for PAK1 and PAK2 undergo apoptosis, while the loss of either protein is well tolerated. However, we found that leukaemic cells explicitly require PAK2 to grow towards an extracellular matrix.

Targeting STATs to overcome drug resistance in chronic myeloid leukemia

In chronic myeloid leukemia BCR-ABL1 mutations and activation of additional pro-oncogenic pathways  cause therapy resistance. Drug combinations covering a broad range of targets may overcome resistance.We investigated a compound that inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines. Succesful drug-combinations blocked multiple signalling cascades and molecules, including STAT3 and STAT5.

Castration-resistant progenitor cell population might be origin of relapse

Androgen-deprivation remains an important therapeutic option for prostate cancer, and thus castration-resistance is lethal.   Despite intense efforts to understand the mechanisms of therapy resistance, the underlying cells remain ill described. We now describe in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration.

New paper on IGF2 promoting colon cancer progression

Stromal-derived IGF2 promotes colon cancer progression via paracrine and autocrine mechanisms.

The insulin-like growth factor (IGF) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. 

New paper on WNT signaling in colorectal carcinoma

The canonical WNT signaling pathway is crucial for intestinal stem cell renewal and aberrant WNT signaling is an early event in colorectal cancer (CRC) development. A new report in the Journal Oncogene now shows for the first time that WNT2 is one of the most significantly induced genes in CRC stroma as compared to normal stroma. We identified cancer-associated fibroblasts (CAFs) as the main source of WNT2, which activated canonical signaling in colon cancer cells in a paracrine fashion.

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