No abstract

Cadherin 6 (CDH6) is significantly overexpressed in advanced ovarian and renal cancers. However, the role of CDH6 in cancer metastasis is largely unclear. Here, we investigated the impact of CDH6 expression on integrin‐mediated metastatic progression. CDH6 preferentially bound to αIIbβ3 integrin, a platelet receptor scarcely expressed in cancer cells, and this interaction was mediated through the cadherin Arginine–glycine–aspartic acid (RGD) motif. Furthermore, CDH6 and CDH17 were found to interact with α2β1 in αIIbβ3low cells. Transient silencing of CDH6, ITGA2B, or ITGB3 genes caused a significant loss of proliferation, adhesion, invasion, and lung colonization through the downregulation of SRC, FAK, AKT, and ERK signaling. In ovarian and renal cancer cells, integrin αIIbβ3 activation appears to be a prerequisite for proper α2β1 activation. Interaction of αIIbβ3 with CDH6, and subsequent αIIbβ3 activation, promoted activation of α2β1 and cell adhesion in ovarian and renal cancer cells. Additionally, monoclonal antibodies specific to the cadherin RGD motif and clinically approved αIIbβ3 inhibitors could block pro‐metastatic activity in ovarian and renal tumors. In summary, the interaction between CDH6 and αIIbβ3 regulates α2β1‐mediated adhesion and invasion of ovarian and renal cancer metastatic cells and constitutes a therapeutic target of broad potential for treating metastatic progression.

The necessity to accurately predict recurrence and clinical outcome in early stage colorectal cancer (CRC) is critical to identify those patients who may benefit from adjuvant chemotherapy. Here, we developed and validated a gene‐based risk‐score algorithm for patient stratification and personalised treatment in early stage disease based on alterations in the secretion of metastasis‐related proteins. A quantitative label‐free proteomic analysis of the secretome of highly and poorly metastatic CRC cell lines with different genetic backgrounds revealed 153 differentially secreted proteins (fold‐change >5). These changes in the secretome were validated at the transcriptomic level. Starting from 119 up‐regulated proteins, a six‐gene/protein‐based prognostic signature composed of IGFBP3, CD109, LTBP1, PSAP, BMP1, and NPC2 was identified after sequential discovery, training, and validation in four different cohorts. This signature was used to develop a risk‐score algorithm, named SEC6, for patient stratification. SEC6 risk‐score components showed higher expression in the poor prognosis CRC subtypes: consensus molecular subtype 4 (CMS4), CRIS‐B, and stem‐like. High expression of the signature was also associated with patients showing dMMR, CIMP+ status, and BRAF mutations. In addition, the SEC6 signature was associated with lower overall survival, progression‐free interval, and disease‐specific survival in stage II and III patients. SEC6‐based risk stratification indicated that 5‐FU treatment was beneficial for low‐risk patients, whereas only aggressive treatments (FOLFOX and FOLFIRI) provided benefits to high‐risk patients in stages II and III. In summary, this novel risk‐score demonstrates the value of the secretome compartment as a reliable source for the retrieval of biomarkers with high prognostic and chemotherapy‐predictive capacity, providing a potential new tool for tailoring decision‐making in patient care.

No abstract

Bfolagía moleieular del oanMtr vesic.alResumen: La etíapatogenia del cáncer vesical s w e smdo dewnocidzb L a pauta del tratamiwita viene determinada par el @&o cclfnim de Ea enk%rWdad.