Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

Although the requirement of neurons for tumor progression has been established, the role of neuronal activity for tumor initiation is poorly understood. Pan and colleagues utilized a mouse model of NF1-mutant optic pathway glioma (OPG) to demonstrate the key role of light-activated neuronal activity in OPG initiation and maintenance. Light stimulation of the optic nerve was required for OPG formation and could be prevented through light deprivation during a key postnatal developmental period. OPG formation was dependent upon NF1-mutant stromal cell NLGN3 shredding, and genetic or pharmacologic NLGN3 inhibition prevented OPG formation.Expert Commentary: This study suggests that NF1 mutations in both the precursor and stromal cells predispose to OPG in a light-activated neuron-dependent manner.Pan Y, Hysinger JD, Barron T, Schindler NF, Cobb O, Guo X, et al. NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature 2021;594:277–82.The intrinsic metabolic identity of the cell of origin of a tumor could provide insight into lineage-rooted cancer metabolic processes and vulnerabilities. Mahendralingam and colleagues performed mass spectrometry-based proteomics on normal human mammary epithelial cell (MEC) subsets—basal, luminal progenitor, and mature luminal cells—obtained from reduction mammoplasties. Metabolic networks showed distinct aggregation by cell type, with basal cells enriched for glycolytic processes, mature luminal cells enriched for pathways related to glutamine and glutathione metabolism, and luminal cells enriched for pathways related to oxidative phosphorylation. Similar findings were observed transcriptionally using scRNA-seq. Functional mitochondrial assays in primary mouse MECs confirmed higher oxygen consumption in luminal cells and distinct morphologies. Luminal cells had larger mitochondria with more cristae. Clonogenicity of MEC types correlated with mitochondrial activity. Inhibitors of glycolysis, mitochondrial complex I, and complex II/III were highly cell-type specific. Finally, analysis of breast cancer datasets supported subtypes sharing metabolic signatures with their cell of origin.Expert Commentary: This study shows that metabolic signatures of breast cancer subtypes are highly conserved and shared with their cell of origin, suggesting targeting lineage-specific metabolic dependencies as a therapeutic strategy.Mahendralingam MJ, Kim H, McCloskey CW, Aliar K, Casey AE, Tharmapalan P, et al. Mammary epithelial cells have lineage-rooted metabolic identities. Nat Metab 2021;3:665–81.Diet has been linked to prostate cancer, and multiple studies have indicated that animal fat intake increases prostate cancer risk. Diet can induce changes in the gut microbiota and metabolites in the gut. Using prostate-specific PTEN knockout mice as a prostate cancer model, Matsushita and colleagues showed that high-fat diet (HFD) altered the gut microbiota composition and promoted cancer growth. Oral administration of an antibiotic mixture (Abx) altered the gut microbiome in HFD-fed mice and downregulated prostate and systemic IGF1 levels. Short-chain fatty acids (SCFA) were reduced in the feces of HFD + Abx mice, and supplementation of SCFAs increased IGF1 production and promoted prostate cancer growth.Expert Commentary: These results suggest that SCFAs produced by intestinal bacteria regulate IGF1 in the host to stimulate proliferation of prostate cancer cells. Altering gut microbiota may reduce the risk of or inhibit the progression of prostate cancer.Matsushita M, Fujita K, Hayashi T, Kayama H, Motooka D, Hase H, et al. Gut microbiota-derived short-chain fatty acids promote prostate cancer growth via IGF1 signaling. Cancer Res 2021;81:4014–26.BRAF-mutant melanoma initially responds to MEK and BRAF inhibitor combinations, however, resistance is inevitable. Although resistance emerges from the minimal residual disease (MRD) population, whether this will occur either through nongenetic or genetic mechanisms is not well understood. Utilizing both patient samples and patient-derived xenograft models, Marin-Bejar and colleagues observed nongenetic resistance in 20% of patients, dependent upon a neural crest stem cell subpopulation. Survival of neural crest stem cells required FAK and retinoic acid signaling. Inhibiting these pathways prevented nongenetic resistance and improved progression-free survival.Expert Commentary: This study demonstrates that nongenetic resistance to MEK and BRAF inhibitors is predictable based on the cellular composition of MRD and is targetable through FAK inhibition.Marin-Bejar O, Rogiers A, Dewaele M, Femel J, Karras P, Pozniak J, et al. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma. Cancer Cell; Published online June 7, 2021; DOI: 10.1016/j.ccell.2021.05.015.Antiangiogenesis agents can induce hemorrhagic regions, the coagulation cascade, and platelet recruitment. Li and colleagues exploited the ability of the vascular disrupting agent Vadimezan to recruit platelets to hemorrhagic areas within tumors and to enhance delivery of immune checkpoint inhibitors. Adoptive transfer of anti-PD-L1 antibody-conjugated platelets led to their preferential recruitment to tumors and lung metastatic lesions following treatment with Vadimezan. This initiated an increase in intratumoral T-cell infiltration and prolonged tumor-free survival in metastatic mouse models.Expert Commentary: The generation of platelet-antibody conjugates as a delivery vehicle is an attractive strategy to enable targeted transport of immune checkpoint inhibitors to tumors. Understanding whether these can be effectively combined with vascular disrupting agents, which are currently being evaluated in the clinic, is now required.Li H, Wang Z, Chen Z, Ci T, Chen G, Wen D, et al. Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis. Nature Commun 2021;12(1):2773. DOI: 10.1038/s41467-021-22674-3.Leucine-rich repeat-containing G protein-coupled receptors 4, 5, and 6 (LGR4/5/6) are important regulators of development and cancer. The biological functions of LGR4/5/6 are primarily attributed to potentiation of Wnt signaling. Yue and colleagues demonstrated a Wnt-independent role of LGR4 in promoting breast cancer metastasis. Genetic or pharmacologic blockade of Wnt signaling did not abrogate effects of LGR4 on metastatic ability of breast cancer cells. Furthermore, LGR4 mutants uncoupled from Wnt signaling maintained the ability to stimulate breast cancer cell migration, invasion, and metastasis as efficiently as wild-type LGR4. Mechanistically, LGR4 bound EGFR, preventing its ubiquitination and degradation. The persistent EGFR signaling mediated by LGR4 increased the metastatic ability of breast cancer cells.Expert commentary: This work elucidates a novel LGR4 oncogenic pathway that enhances EGFR signaling independently of Wnt activity to promote cancer metastasis.Yue F, Jiang W, Ku AT, Young AIJ, Zhang W, Souto EP, et al. A Wnt-independent LGR4-EGFR signaling axis in cancer metastasis. Cancer Research; Published OnlineFirst June 7, 2021; DOI: 10.1158/0008-5472.CAN-21-1112.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.