Oncogenic SWI/SNF in Squamous Cancers
Stem-like regenerative proliferation and blocked differentiation correlate with outcome in head and neck squamous cell carcinoma (HNSCC). While genomic amplification of p63 has been linked to these phenotypes, the molecular underpinnings driving these aberrant programs remain unclear. Saladi and colleagues now show that ACTL6A, a subunit of the SWI/SNF complex, is frequently amplified and highly expressed together with p63 in HNSCC. Moreover, ACTL6A binds to p63 and this complex cooperatively controls transcriptional programs that promote proliferation and suppress differentiation, in part through activation of oncogenic YAP activity. Importantly, ACTL6A and YAP activation are correlated with poor patient survival in primary HNSCC. This study therefore establishes a molecular mechanism for p63-mediated epigenetic regulation and uncovers a critical oncogenic role for SWI/SNF, which is largely viewed as a tumor suppressor in human cancer.
Preventing Radiation-Induced Gains in GBM
MDA-9 or syntenin is overexpressed in glioblastoma multiforme (GBM) and its expression correlates inversely with survival and response to radiation therapy. Kegelman and colleagues silenced MDA-9 in glioblastoma cells, rendering them sensitive to radiation, reducing invasion postradiation, and downregulating radiation-induced Src and EGFRvIII signaling. The authors next used fragment-based drug design and NMR to generate a first-in class small-molecule inhibitor of the PDZ1 domain of MDA-9 (PDZ1i). PDZ1i inhibited protein binding between MDA-9/syntenin and EGFRvIII, promoting GBM-specific radiosensitization, while sparing normal astrocytes. In vivo treatment with PDZ1i alone resulted in smaller, less invasive tumors and enhanced survival. Further, survival was improved in combining PDZ1i with radiation as compared with radiation alone. Thus, MDA-9 directly mediates invasion of GBM following radiation and shows it as a “druggable” target for GBM therapy.
Radioimmunotherapy for Pancreatic Cancer
Azad and colleagues treated pancreatic ductal adenocarcinoma (PDAC) with concomitant radiation and anti-PD-L1 antibodies, observing impressive tumor growth delay and some regression after high but not low radiation doses. This response depended on increased numbers of activated CD8+ T cells in treated tumors, with CD11b+Gr1+ myeloid cells and FOXP3+ T regulatory cells showing decreased abundance. Combination radioimmunotherapy decreased PDAC metastasis to the liver, an effect that involved radiation-induced expression of PDAC PD-L1, and was dependent on JAK/Stat1 but not Stat3, both in vitro and in vivo. Mathematical modeling of tumor treatment data suggested anti-PD-L1 treatment, combined early but not late with radiation, reprogrammed the tumor microenvironment to a more inflammatory state. This increased the recruitment of CD8+ T cells to kill PDAC tumor cells and supports clinical trials that explore radioimmunotherapy in PDAC.
Sodium Channels in Gastric Cancer
Qian and colleagues observed that the sodium channel subunit SCNN1B was silenced by promoter hypermethylation in gastric cancer cells and tumor tissues. Higher expression of SCNN1B in late stage gastric cancer patients was identified as a prognostic factor for enhanced survival. In vitro and in vivo studies demonstrated that SCNN1B overexpression suppressed cancer cell pathophysiology. Mechanistically, SCNN1B caused degradation of the endoplasmic reticulum chaperone GRP78 and activation of the unfolded protein response (UPR), leading to caspase-dependent apoptosis. Additionally, gastric cancer cells were sensitized to the UPR-inducing drug tunicamycin upon overexpression of SCNN1B. Overexpression of GRP78 abolished the tumor suppressive effects of SCNN1B, and silencing GRP78 enhanced tumor suppressive effects of SCNN1B. Thus, these data identify a novel tumor suppressor SCNN1B as a candidate survival biomarker in gastric cancer patients.
Age-Dependent Toxicities in Cancer Therapy
Compared with adults, children treated with chemotherapy and radiation are more prone to developing toxicities affecting brain, heart, and kidneys. Sarosiek and colleagues demonstrate that this vulnerability is underscored by differences in mitochondrial responsiveness to trigger apoptosis in response to relevant stimuli. Indeed, the mitochondrial apoptotic machinery was absent in many adult tissues, while their embryonic and postnatal counterparts were primed for apoptosis in response to genotoxic stress. Thus, apoptotic priming decreases during development and may explain the hypersensitivity of young tissues to chemoradiotherapy. Developmentally regulated mitochondrial priming was controlled in part by Myc, which selectively drove the expression of proapoptotic genes in embryonic tissues. Importantly, this vulnerability could be overcome by unpriming the mitochondria of young tissues (knockout of apoptotic regulators), suggesting possible targets for therapeutic modulation.
ROR1 and MAYA: Novel Targets against Bone Metastasis
Li and colleagues demonstrate that the receptor tyrosine kinase-like orphan receptor ROR1 is upregulated and correlated with poor outcome in triple-negative breast cancer (TNBC). CRISPR-Cas9-mediated deletion of ROR1 reduced cell proliferation and bone metastasis of TNBC cells and significantly downregulated established YAP1-regulated genes. Using pulldowns and biochemistry in conjunction with mass spectrometry, the authors demonstrate that (i) neuregulin induced heterodimerization of HER3-ROR1; (ii) ROR1 mediated novel phosphorylation of HER3 on Tyr1307 (p-HER3 Tyr1307); and (iii) p-HER3 Tyr1307 led to assembly of a long noncoding RNA-containing complex (LLGL2-MAYA-NSUN6) that methylated and inhibited YAP suppressor MST1 kinase, activating YAP-driven tumor proliferation. Inoculation of mice with MAYA lncRNA reduced the bone tumor burden TNBC, also suggesting that targeting ROR1 could potentially interfere with the HER3-ROR1 heterodimerization and block activation of this bone metastasis driving signaling module.
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.