Highlights of This Issue

Abstract

Mastermind-like 3 (MAML3) is a known co-activator of NOTCH signaling. Heynen and colleagues find an additional and unexpected role for MAML3 in retinoic acid signaling in neuroblastoma, which is used clinically to induce differentiation in this cancer. Elevated expression of MAML3 leads to loss of activation of a subset of retinoic acid receptor target genes and as a consequence blocks retinoic acid-induced differentiation. MAML3 also has retinoic acid independent functions in neuroblastoma through upregulation of IGF2, which activates AKT signaling downstream of IGF1R. These data shed light on why MAML3 is mutated in multiple cancers.Here, the functional and molecular consequences of cytotoxic chemotherapy treatment on pancreatic cancer-associated fibroblasts (CAFs) were investigated. Chemotherapy treated CAFs enhanced tumor cell viability, migration and invasion in vitro as well as tumor growth in vivo compared to treatment naïve CAFs. A pro-inflammatory gene expression signature mediated by stress-associated MAPK was identified in chemotherapy treated CAFs. Stress-associated MAPK inhibitors decreased expression of inflammatory mediators and reduced tumor cell viability, migration, and invasion in vitro as well as tumor growth in vivo. These results describe a novel molecular response to chemotherapy in pancreatic CAFs and represent a future therapeutic target.Increased signaling from growth-factor receptors and stress-related kinases plays a role in endocrine resistance, a major challenge in the treatment of estrogen receptor-positive breast cancer (BC) patients. An integrative in silico transcriptomic/cistromic approach implicated the AP-1 transcription complex as a signaling node in endocrine resistance. When AP-1 activity was inhibited by an inducible genetic approach in BC cells grown in vitro and in vivo, the blockade enhanced sensitivity to endocrine therapy, delayed resistance onset, and overcame the growth of tamoxifen-resistant tumors. These data demonstrate AP-1 as a driver of endocrine resistance and offer new perspectives for innovative treatment and biomarker research.The article by Kallifatidis and colleagues defines the heterotypic Src-mediated transactivation of the epidermal growth factor receptor (EGFR) by the atypical chemokine receptor, CXCR7, in prostate cancer. The highlight of the discovery is that the scaffold protein β-Arrestin 2 was found to regulate this transactivation and reduce the phosphorylation of EGFR at Tyrosyl 1110, one of the seven cytoplasmic phosphorylation domains of EGFR. Further, down-regulation of β-Arrestin 2 leads to increased mitogenic activity, decreased p21, and re-location of EGFR to the nucleus. This study reveals important tumor suppressor activity of β-Arrestin 2 in the context of EGFR signaling.