Deubiquitinating enzymes (DUBs) are linked to cancer progression and dissemination, yet less is known about their regulation and impact on epithelial-mesenchymal transition (EMT). An integrative trans Show more
Deubiquitinating enzymes (DUBs) are linked to cancer progression and dissemination, yet less is known about their regulation and impact on epithelial-mesenchymal transition (EMT). An integrative translational approach combining systematic computational analyses of The Cancer Genome Atlas cancer cohorts with CRISPR genetics, biochemistry and immunohistochemistry methodologies to identify and assess the role of human DUBs in EMT. We identify a previously undiscovered biological function of STAM-binding protein like 1 (STAMBPL1) deubiquitinase in the EMT process in lung and breast carcinomas. We show that STAMBPL1 expression can be regulated by mutant p53 and that its catalytic activity is required to affect the transcription factor SNAI1. Accordingly, genetic depletion and CRISPR-mediated gene knockout of STAMBPL1 leads to marked recovery of epithelial markers, SNAI1 destabilisation and impaired migratory capacity of cancer cells. Reversely, STAMBPL1 expression reprogrammes cells towards a mesenchymal phenotype. A significant STAMBPL1-SNAI1 co-signature was observed across multiple tumour types. Importantly, STAMBPL1 is highly expressed in metastatic tissues compared to matched primary tumour of the same lung cancer patient and its expression predicts poor prognosis. Our study provides a novel concept of oncogenic regulation of a DUB and presents a new role and predictive value of STAMBPL1 in the EMT process across multiple carcinomas. Show less
Chondrosarcomas are malignant tumors of chondrocytes and represent the second most common type of primary bone tumors. Within the context of normal chondrogenesis, this review summarizes results from Show more
Chondrosarcomas are malignant tumors of chondrocytes and represent the second most common type of primary bone tumors. Within the context of normal chondrogenesis, this review summarizes results from recent research outlining the key molecular changes that occur during the development of this sarcoma type. Current data support the notion that a two-hit scenario, common to many tumors, also underlies chondrosarcoma formation. First, early-stage mutations alter the normal proliferation and differentiation of chondrocytes, thereby predisposing them to malignant transformation. These early-stage mutations, found in both benign cartilaginous lesions and chondrosarcomas, include alterations affecting the IHH/PTHrP and IDH1/IDH2 pathways. As they are not observed in malignant cells, mutations in the EXT1 and EXT2 genes are considered early-stage events providing an environment that alters IHH/PTHrP signaling, thereby inducing mutations in adjacent cells. Due to normal cell cycle control that remains active, a low rate of malignant transformation is seen in benign cartilaginous lesions with early-stage mutations. In contrast, late-stage mutations, seen in most malignant chondrosarcomas, appear to induce malignant transformation as they are not found in benign cartilaginous lesions. These late-stage mutations primarily involve cell cycle pathway regulators including p53 and pRB, two genes that are also known to be implicated in numerous other human tumor types. Now the key genetic alterations involved in both early and late stages of chondrosarcoma development have been identified, focus should be shifted to the identification of druggable molecular targets for the design of novel chondrosarcoma-specific therapies. Show less