Highlights of This Issue

Abstract

Aberrant glycosylation is one of the hallmarks of cancer, and cancer cell glycans serve as tumor biomarkers. Glycosylation modulates the functions of glycoproteins; however, the functional significance of protein glycosylation in cancer progression remains poorly defined. Here, β1,6GlcNAc-branched N-glycan–suppressing and N-glycan–defective β4-integrin expressing cell model systems were used to demonstrate that N-glycosylation of β4-integrin contributes to tumor progression. It was determined that β4-integrin clustering by galectin-3–mediated cross-linking of β1,6GlcNAc-branched N-glycans on β4-integrin activates PI3K/Akt signaling, thereby promoting cancer cell behavior. Thus, N-glycosylation of β4-integrin represents a potential therapeutic target for cancer.Adaptive cellular responses induced by cancer therapeutics are emerging as an important mechanism for acquired resistance to chemotherapies. In this study, Fang and colleagues identified olaparib-induced FOXM1 expression as an adaptive response that induces the expression of homologous recombination (HR) repair genes. Knockdown of olaparib-induced FOXM1 expression by RNAi or pharmacologic inhibition by thiostrepton downregulates the expression of HR repair genes, increases DNA damage and PARP1 trapping, and enhances sensitivity to olaparib. This study highlights the important role of FOXM1 in the adaptive response to olaparib, and that targeting the adaptive response mediated by FOXM1 extends the efficacy of PARP inhibitors.A major problem that limits the effectiveness of cancer chemotherapeutics is the development of drug resistance. Recently, dysregulation of the Hippo pathway core component LATS has been implicated in this process, but its underlying mechanisms remain unknown. Now, Yeung and colleagues functionally characterize a novel signaling pathway in which anti-tubulin drugs activate Cdk1 and phosphorylate LATS, which then binds prolyl isomerase Pin1 and inhibits its anti-apoptotic function. Importantly, loss of LATS phosphorylation reduces taxol-induced cell death. Together, this work provides new insight into the anti-tubulin drug response and demonstrates the Cdk1-LATS-Pin1 signaling axis as a promising target for treatment.ATP-binding cassette (ABC) transporters are a known mechanism of drug resistance, however multiple clinical trials targeting ABCB1 have failed. Thus, it is hypothesized here, that ABC transporters aggravate cancer biology by exporting endogenous lipid mediator sphingosine-1-phosphate (S1P) regardless of drugs. S1P generated by SphK1 and exported via ABCC1 aggravated cancer in a malicious feed-forward manner by amplifying the S1P axis in vitro, and worsened cancer progression in vivo. Patients with high levels of both SphK1 and ABCC1 have worse survival. While, ABCB1, which does not export S1P, did not demonstrate these findings. This suggests a critical role for the S1P axis in breast cancer progression.