graphic

Paternally expressed gene 10 (PEG10) primarily expressed in the placenta is crucial for embryonic development. PEG10 isoforms promote the progression of prostate cancer to a highly lethal androgen receptor (AR)–negative phenotype. Shapovalova and colleagues found that PEG10 expression was not restricted to AR-null disease but was also expressed in prostate cancer with constitutively active AR-splice variants. Using the cancer specificity of the PEG10 promoter, the authors created a molecular genetic imaging tool to detect these highly lethal prostate cancer subtypes. The imaging strategy incorporated an optimized PEG10 promoter and a two-step transcriptional amplification element for enhanced output. The final imaging construct allowed precise tumor detection in PEG10-positive castration-resistant prostate cancer animal models by near infrared and PET/CT imaging.

Expert Commentary: Preclinical proof of concept is provided, indicating that the PEG10 promoter is a potent and specific tool that can be utilized for noninvasive detection of aggressive prostate cancer subtypes.

Shapovalova M, Lee JK, Li Y, Vander Griend DJ, Coleman I, Nelson PS, et al. PEG10 promoter–driven expression of reporter genes enables molecular imaging of lethal prostate cancer. Cancer Res 2019;79:5668–80.

graphic

High-grade gliomas are aggressive tumors of the central nervous system. Venkatesh and colleagues demonstrated that gliomas express synaptic genes and have synaptic structures. GFP-positive Histone H3K27M–mutant glioma transplanted into hippocampus showed clear neuron to glioma synapses, with electrophysiological properties reminiscent of synapses formed with normal cells. Several neurophysiological assays identified activity-dependent potassium currents and gap junction–coupled glioma networks. Two-photon calcium imaging elucidated a functional glioma network with glutaminergic chemical synapses. Glioma cells expressing blue-light channel rhodopsin protein displayed clear depolarization and proliferation in response to blue-light, and coculture of neurons with glioma markedly increased proliferation. Pharmacological inhibition of synaptic transmission blocked proliferation in vivo. Electrocorticography in three glioma patients supported the presence of neuronal hyperexcitability within glioma-infiltrated regions compared with normal brain.

Expert Commentary: This study shows that glioma is an electrically active tissue with complex neural networks involving tumor and normal brain, where depolarization induces proliferation. Targeting this electrical activity is an attractive new approach to treatment.

Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, et al. Electrical and synaptic integration of glioma into neural circuits. Nature 2019;573:539–45.

graphic

The vast majority of new drugs fail in clinical trials due to lack of efficacy or unexpected toxicities. Lin and colleagues tested the hypothesis that many of these novel, often first-in-class, small molecules fail during clinical testing because of incorrectly identified mechanisms of action. Using CRISPR-Cas9 technology, they investigated drug-target relationships for a number of small molecules currently being evaluated clinically. They showed that many of these drug targets, previously validated by RNAi, were not required for the proliferation of relevant cancer cell lines. Further, efficacy of drugs being evaluated was unaffected by genomic deletion of that drug's target, suggesting that the drugs were killing cancer cells via some nonspecific manner. Lin and colleagues went on to identify the correct target for one of these drugs, OTS964, as CDK11 and showed that cancer cell lines addicted to CDK11 expression were quite sensitive to OTS964.

Expert Commentary: Stringent, preclinical, genetic validation of novel drug targets will improve the success rate of clinical trial candidates.

Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med 2019;11. doi: 10.1126/scitranslmed.aaw8412.

graphic

Transcriptional enhancers regulate the temporal and spatial control of gene expression, however, mechanisms that govern long-range enhancer function during normal and malignant processes remain elusive. Belver and colleagues identified changes in chromatin accessibility in regulation of MYC expression in T-cell lymphoblastic leukemia (T-ALL). A MYC-specific long-range T-cell enhancer, N-Me, was shown to play a central role. This enhancer displayed active modifications in chromatin accessibility during T-cell specification and maturation as well as an abnormal chromatin accessibility in both mouse and human T-ALL cells. The authors found that nucleosome eviction driven by the transcription factor Gata3 dynamically regulated the function of the N-Me enhancer. Furthermore, this process was necessary and sufficient for initiation and development of T-ALL induced by NOTCH-1.

Expert Commentary: This study suggests that dysregulation of chromatin access at specific enhancers contributes to leukemia tumorigenesis and may lead to novel cancer targets.

Belver L, Yang AY, Albero R, Herranz D, Brundu FG, Quinn SA, et al. Gata3-controlled nucleosome eviction drives MYC enhancer activity in T-cell development and leukemia. Cancer Discovery; Published first September 13, 2019; doi: 10.1158/2159-8290.CD-19-0471.

graphic

Metastatic spread of breast cancer to bone occurs in around 50% of patients and is a significant predictor of cancer-related death. Using an ex vivo bone culture model, Romero-Moreno and colleagues demonstrated that healthy bone can secrete factors that induce cancer cell dormancy, whereas cancer cells prime the bone microenvironment to produce factors that induce colonization. They identified CXCL5 as a factor that could induce cancer cell proliferation in the bone microenvironment and awaken quiescent cells from dormancy.

Expert Commentary: Colonization of cancer cells at metastatic sites is the rate-limiting step of the metastatic process. This study identifies the CXCL5/CXCR2 axis as a potential therapeutic target for preventing growth and colonization in the bone microenvironment.

Romero-Moreno R, Curtis KJ, Coughlin TR, Cristina Miranda-Vegara M., Dutta S, Natarajan A, et al. The CXCL5/CXCR2 axis is sufficient to promote breast cancer colonization during bone metastasis. Nat Commun 2019;10:4404. doi: 10.1038/s41467-019-12108-6.

graphic

One-third of melanoma patients develop brain metastases that are resistant to chemotherapy, highlighting the clinical need for therapeutics. Zou and colleagues isolated brain tropic cell lines with high or low metastatic potential from resected metastatic brain tumor tissue. Using RNA-seq and bioinformatics, they demonstrated that the peroxisome proliferator-activated receptor-γ (PPARγ) signaling pathway was enriched in brain tumor metastases. Early on, invading tumor cells were associated with astrocytes. This association persisted until the formation of larger metastases. Astrocytes produce a high concentration of polyunsaturated fatty acids, known as PPARγ ligands. Thus, astrocytes enhance the proliferation of tumor cells in the brain by producing and secreting polyunsaturated fatty acids. Consistent with these findings, PPARγ signaling was significantly higher in clinical brain tumor metastases than in matched primary tumors. Leveraging these findings, they showed that PPARγ antagonists attenuate growth of brain tumor cells in vitro and in vivo.

Expert Commentary: PPARγ antagonists represent a novel way to target brain metastases.

Zou Y, Watters A, Cheng N, Perry CE, Xu K, Alicea GM, et al. Polyunsaturated fatty acids from astrocytes activate PPAR gamma signaling in cancer cells to promote brain metastasis. Cancer Discovery; Published first October 2, 2019; doi: 10.1158/2159-8290.CD-19-0270.

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.