Centrosome Amplification Disrupts Autophagy
Denu et al. Page 33
Centrosomes organize the cellular microtubule network, which requires precise regulation to avoid disruptions in intracellular trafficking. However, centrosome amplification (CA) is a common feature of human cancers, which suggests the possibility that cancers harboring CA may also harbor intrinsic weaknesses that could be exploited in the clinic. Here, Denu and colleagues report that cancer cells with CA exhibit an increased reliance on autophagy, and accumulate supernumerary autophagosomes relative to cells without CA. The authors demonstrate that this accumulation was due to a defect in autophagosome trafficking to lysosomes as a result of the disrupted microtubule networks, and cells with CA are sensitized to genetic and pharmacologic targeting of the autophagy cascade. Taken together, the data suggest that CA could be used as a predictive biomarker to identify patients who would derive benefit from treatment with autophagy inhibitors.
Kynurenine Pathway in Cisplatin-Resistant Lung Cancer
Nguyen et al. Page 105
Cisplatin resistance (CR) is a pervasive hurdle in the clinical management of lung cancer, but CR cells display alterations in oxidative metabolism (OXMET) which may represent a means of enhancing or extending the efficacy of cisplatin therapy. In this study, Nguyen and colleagues show that CR lung cancer cells also upregulate IDO1, the first step in the kynurenine pathway, in response to increased intracellular reactive oxygen species (ROS) generated by OXMET. Ablation or inhibition of IDO1 caused an increase in ROS abundance, which subsequently impeded proliferation in CR lung cancer cells. Finally, increased abundance of immunosuppressive regulatory T cells was observed in mice bearing CR tumors, owing to the role of kynurenine in T cell reprogramming. These observations collectively shed new light on both the biology of CR lung cancers and the potential utility of IDO1 inhibitors, which are currently under active investigation as experimental therapeutics.
Reverting Colorectal Cancer Cells to Normal-like Cells
Lee et al. Page 118
Genetic and epigenetic alterations progressively rewire gene expression networks in tumor cells, leading to the emergence of malignant phenotypes. Here, Lee and colleagues demonstrate the feasibility of reversing colorectal cancer cells to post-mitotic, normal-like cells via an epigenetic mechanism. To identify transcription factors (TF) that control the differentiated state, the authors constructed a gene regulatory network using transcriptomic data from normal colon mucosa. Network analysis identified the histone methyltransferase SETDB1 as a key disruptor of the normal differentiation: expression of SETDB1 impeded the function of key lineage-determining TFs, thus undermining the differentiated state. Accordingly, depletion of SETDB1 from colorectal cancer cells restored lineage TF function and reverted the cellular transcriptome back to a normal-like state. Taken together, the data provide proof of concep. for a new therapeutic method that returns cancer cells to a non-malignant state rather than seeking to eliminate them through cytotoxic modalities.
Role of PRMT6 in Lung Tumor Progression
Avasarala et al. Page 166
Amplification of protein arginine methyltransferases (PRMTs), including PRMT6, is a known indicator of poor prognosis in lung cancer. However, given the limited substrate specificity of PRMT6, its precise role in regulating tumor cell biology is poorly defined. Using a novel, inducible in vivo model of PRMT6 over-expression, Avasarala and colleagues have now defined a new, non-catalytic role for PRMT6 in lung cancer tumorigenesis and disease progression. Analysis of PRMT6-associated proteins identified a previously unknown interaction between PRMT6 and ILF2, which collaborated to promote accumulation of pro-tumorigenic tumor-associated macrophages (TAM). Mechanistically, PRMT6-ILF2 signaling was shown to directly regulate the expression of macrophage migration inhibitory factor (MIF), which was recently shown to drive alternative activation of TAM. This study offers the first in vivo insight into the disease relevance of PRMT6 in lung cancer and presents a novel mouse model to further define its in vivo functions in the lung.