TWIST1 Inhibition in Lung Cancer
Epithelial plasticity programs such as epithelial-mesenchymal transition (EMT) have established roles late in cancer progression, driving metastasis and treatment resistance depending on the cancer type. A less appreciated activity of epithelial plasticity programs directed by EMT transcription factors occurs very early during epithelial tumorigenesis to suppress oncogene-induced senescence and oncogene-induced apoptosis. The EMT transcription factor TWIST1 is critical for non-small cell lung cancer (NSCLC) tumorigenesis. Yochum and colleagues performed a chemical-bioinformatic screen for inhibitors of TWIST1 and discovered that the harmala alkaloid, harmine, inhibited multiple TWIST1-dependent functions in vitro. Harmine preferentially degraded TWIST1 specifically in TWIST1-E2A heterodimers. Harmine had anticancer activity against a range of oncogene-driven NSCLC cells in vitro and in vivo, eliciting senescence and apoptosis. These findings suggest that pharmacologic inhibition of TWIST1 may be useful in NSCLC.
A Candidate Immunotherapeutic Target in Neuroblastoma
High-risk neuroblastoma is an aggressive cancer with a poor prognosis. Neuroblastoma arises from neural crest progenitor cells of the developing sympathetic nervous system and continues to express lineage-specific surface markers. This provides rationale to develop immunotherapies targeting these markers. Bosse and colleagues compared RNA-sequencing data from primary high-risk neuroblastoma tumors against normal tissues and identified nine candidate immunotherapeutic targets among the 296 differentially expressed genes. The extracellular glycosylphosphatidylinositol-anchored signaling co-receptor glypican 2 (GPC2) was selected for further studies based on prior demonstration of increased expression in pediatric tumors, including high-risk neuroblastomas, and its validation as a targetable protein in immune-based therapies. In addition, approximately 40% of high-risk neuroblastomas demonstrated somatic gain of chromosome 7q, which harbors the GPC2 locus, promoting enhanced GPC2 expression. Further, GPC2 was transcriptionally activated by the MYCN proto-oncogene, resulting in increased GPC2 expression in MYCN-amplified tumors. GPC2 knockdown led to decreased cell growth, decreased colony formation, and induction of apoptosis. A GPC2-targeting antibody-drug conjugate was developed and demonstrated cytotoxicity to GPC2-expressing neuroblastoma cells both in vitro and in vivo. These studies suggest that GPC2 is a potential immunotherapeutic target in high-risk neuroblastoma.
Targeting the Microenvironment in Glioblastoma
High-grade gliomas including glioblastomas have a poor prognosis and few effective treatment options. In addition to therapies that target intrinsic mechanisms of glioma cells, therapies are needed that target tumor microenvironment elements, such as neuronal activity, that promote glioma tumorigenesis. Neuroligin-3 (NLGN3) is a synaptic cell adhesion molecule that Venkatesh and colleagues previously reported was secreted by active neurons and promoted glioma growth. Here, they report that patient-derived pediatric and adult glioblastoma xenografts show impaired growth in Nlgn3 knockout mice. NLGN3 exerted its effects by stimulating several oncogenic pathways such as focal adhesion kinase activation upstream of PI3K-mTOR and induced transcriptional upregulation of several synapse-related genes in glioma cells. In silico analysis identified proteases MMP9 and ADAM10 as candidates that cleaved NLGN3 from the synaptic cleft, releasing a peptide that triggered glioma growth and proliferation. In a conditional knockout mouse model of Adam10, secretion of NLGN3 was significantly abrogated in neurons. Pharmacological inhibition of ADAM10 inhibited growth of pediatric glioblastoma xenografts in vivo, suggesting targeting the microenvironment as a therapeutic strategy in high-grade glioma.
Linking Inflammation and Autoimmunity to Cancer
Epithelial-mesenchymal transition (EMT), regulated by transcription factors of the Snail and ZEB families, is associated with progression and poor outcome in basal-like breast cancer. Lee and colleagues reveal a previously unappreciated link between cancer metastasis and A20, a ubiquitin editing enzyme with functions in inflammation and autoimmunity. A20 was highly expressed in basal-like tumors and correlated with poor outcome in clinical datasets. A20 monoubiquitylated Snail1 at three lysine residues, reducing its affinity to GSK3β kinase, a negative regulator of Snail1. The increased stability of Snail1 induced EMT in mammary epithelial cells and lung metastasis in murine models of aggressive breast cancer. A20 depletion reduced the ability of breast cancer cells to generate mammospheres and increased their sensitivity to chemotherapy. Thus, A20 has a critical role in EMT and inflammatory signaling in breast cancer progression.
HCC Derived from EpCAM+ Ductal Cells
Matsumoto and colleagues evaluated proliferating ductal cells (PDC) as cells of origin for hepatocellular carcinoma (HCC). In the inflamed liver, PDC that expressed EpCAM, an established surface and cancer stem cell marker, could give rise to HCC. EpCAM-expressing PDC were labeled in a new EpcamCreERT2 transgenic mouse model and traced in a chemically induced liver injury model. Stepwise accumulation of genetic alterations in EpCAM-positive cells was induced by the mutagenesis activity of activation-induced cytidine deaminase using conditional transgenic mice. In the chemically damaged liver, PDC differentiated into cholangiocytes and not hepatocytes. However, after 8 months of chemical assault, EpCAM-positive PDC generated HCC. Histologically, tumors showed ductule-like structures resembling human cholangiolocellular carcinoma (CLC), with serial transitions from PDC-like CLC cells to hepatocyte-like HCC cells. Thus, HCC could originate from EpCAM-expressing PDC, indicating the potential existence of stem/progenitor-derived hepatocarcinogenesis.
A Novel Preclinical Model for Rare Embryonal Tumors
Embryonal tumors with multilayered rosettes (ETMR) are rare infant brain tumors characterized by amplification of a microRNA cluster on Chr19q13.41 and high expression of the stem cell marker Lin28A. Profiling primary ETMR tumors, Neumann and colleagues found recurrent mutations activating both WNT and SHH pathways. Coactivation of both pathways in a mouse model generated large forebrain tumors resembling primitive neuroectodermal tumors. Apical radial glia and apical intermediate progenitor (Sox2+/Pax6+) cells of the cortical ventricular zone were identified as cells of origin. Cross-species profiling confirmed that mouse tumors most resembled ETMR and expressed Lin28A. Both neurospheres from the murine ETMR and patient-derived xenografts were sensitive to arsenic trioxide, a SHH pathway inhibitor. This study provides a novel animal model for a rare but lethal pediatric brain tumor and offers potential new treatment paradigms.
Note: Breaking Advances 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.
- ©2017 American Association for Cancer Research.
Volume 77, Issue 21
