Oncologies
Abstract
To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor–negative (HR–) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase–relevant (TKR), and mesenchymal stem–like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR– breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab–drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.
Authors
Lie Chen, Cui-Cui Liu, Si-Yuan Zhu, Jing-Yu Ge, Yu-Fei Chen, Ding Ma, Zhi-Ming Shao, Ke-Da Yu
Abstract
Neuroblastomas have shed light on the differentiation disorder that is associated with spontaneous regression or differentiation in the same tumor at the same time. Long noncoding RNAs (lncRNAs) actively participate in a broad spectrum of biological processes. However, the detailed molecular mechanisms underlying lncRNA regulation of differentiation in neuroblastomas remain largely unknown. Here, we sequenced clinical samples of ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. We compared transcription profiles of neuroblastoma cells, ganglion cells, and intermediate state cells; verified the profiles in a retinoic acid–induced cell differentiation model and clinical samples; and screened out the lncRNA ADAMTS9 antisense RNA 2 (ADAMTS9-AS2), which contributed to neuroblastoma differentiation. ADAMTS9-AS2 upregulation in neuroblastoma cell lines inhibited proliferation and metastatic potential. Additional mechanistic studies illustrated that the interactions between ADAMTS9-AS2 and LIN28B inhibited the association between LIN28B and primary let-7 (pri-let-7) miRNA, then released pri-let-7 into cytoplasm to form mature let-7, resulting in the inhibition of oncogene MYCN activity that subsequently affected cancer stemness and differentiation. Furthermore, we showed that the observed differential expression of ADAMTS9-AS2 in neuroblastoma cells was due to N6-methyladenosine methylation. Finally, ADAMTS9-AS2 upregulation inhibited proliferation and cancer stem-like capabilities in vivo. Taken together, these results show that ADAMTS9-AS2 loss leads to malignant neuroblastoma by increasing metastasis and causing dysfunctional differentiation.
Authors
Yun Liu, Jun Zhang, Fang Cao, Xiaobao Dong, Jie Li, Yanna Cao, Zhanglin Li, Yan Guo, Jie Yan, Yuanyuan Liu, Qiang Zhao
Abstract
Histone deacetylase (HDAC) inhibitors have garnered considerable interest for the treatment of adult and pediatric malignant brain tumors. However, owing to their broad-spectrum nature and inability to effectively penetrate the blood-brain barrier, HDAC inhibitors have failed to provide substantial clinical benefit to patients with glioblastoma (GBM) to date. Moreover, global inhibition of HDACs results in widespread toxicity, highlighting the need for selective isoform targeting. Although no isoform-specific HDAC inhibitors are currently available, the second-generation hydroxamic acid–based HDAC inhibitor quisinostat possesses subnanomolar specificity for class I HDAC isoforms, particularly HDAC1 and HDAC2. It has been shown that HDAC1 is the essential HDAC in GBM. This study analyzed the neuropharmacokinetic, pharmacodynamic, and radiation-sensitizing properties of quisinostat in preclinical models of GBM. It was found that quisinostat is a well-tolerated and brain-penetrant molecule that extended survival when administered in combination with radiation in vivo. The pharmacokinetic-pharmacodynamic-efficacy relationship was established by correlating free drug concentrations and evidence of target modulation in the brain with survival benefit. Together, these data provide a strong rationale for clinical development of quisinostat as a radiosensitizer for the treatment of GBM.
Authors
Costanza Lo Cascio, Tigran Margaryan, Ernesto Luna-Melendez, James B. McNamara, Connor I. White, William Knight, Saisrinidhi Ganta, Zorana Opachich, Claudia Cantoni, Wonsuk Yoo, Nader Sanai, Artak Tovmasyan, Shwetal Mehta
Abstract
BACKGROUND Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown.METHODS This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible.RESULTS Seventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication.CONCLUSION The unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options.FUNDING US National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.
Authors
Carolina Caro-Vegas, Alice Peng, Angelica Juarez, Allison Silverstein, William Kamiyango, Jimmy Villiera, Casey L. McAtee, Rizine Mzikamanda, Tamiwe Tomoka, Erin C. Peckham-Gregory, Razia Moorad, Carrie L. Kovarik, Liane R. Campbell, Parth S. Mehta, Peter N. Kazembe, Carl E. Allen, Michael E. Scheurer, Nmazuo W. Ozuah, Dirk P. Dittmer, Nader Kim El-Mallawany
Abstract
Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type-specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by two orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.
Authors
Jiayu Chen, Qizhi Zheng, Jessica L. Hicks, Levent Trabzonlu, Busra Ozbek, Tracy Jones, Ajay M. Vaghasia, Tatianna C. Larman, Rulin Wang, Mark C. Markowski, Samuel R. Denmeade, Kenneth J. Pienta, Ralph H. Hruban, Emmanuel S. Antonarakis, Anuj Gupta, Chi V. Dang, Srinivasan Yegnasubramanian, Angelo M. De Marzo
MIG6 loss confers resistance to ALK/ROS1 inhibitors in NSCLC through EGFR activation by low-dose EGF
Abstract
Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1)-positive non-small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR-Cas9 knockout screening was performed using an ALK-positive NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor-suppressor genes, such as NF2 or MED12, and multiple new candidate genes. Among them this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly MIG6 loss induced the resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration through the upregulation of MAPK and PI3K/Akt/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this confirmed that MIG6 loss induces resistance to ROS1-TKIs in ROS1-positive cell lines. This study found a novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.
Authors
Nobuyuki Kondo, Takahiro Utsumi, Yuki Shimizu, Ai Takemoto, Tomoko Oh-hara, Ken Uchibori, Sophia Subat-Motoshi, Hironori Ninomiya, Kengo Takeuchi, Makoto Nishio, Yasunari Miyazaki, Ryohei Katayama
Abstract
Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironment. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1α stability and activating the HIF-1α signaling pathway. However, whether other metabolites regulate HIF-1α stability remains unclear. Here, we reported that the enzyme in phenylalanine/tyrosine catabolism glutathione S-transferase zeta 1 (GSTZ1) deficiency led to accumulation of succinylacetone, which was structurally similar to α-ketoglutarate. Succinylacetone competed with α-ketoglutarate for PHD2 binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1α, thus resulting in its stabilization and consequent expression of vascular endothelial growth factor (VEGF). Our findings suggest that GSTZ1 may serve as an important tumor suppressor owing to its ability to inhibit the HIF-1α/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1α inhibitor combined with anti-PD-L1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in Gstz1-knockout mice, suggesting a potentially actionable strategy for HCC treatment.
Authors
Huating Luo, Qiujie Wang, Fan Yang, Rui Liu, Qingzhu Gao, Bin Cheng, Xue Lin, Luyi Huang, Chang Chen, Jin Xiang, Kai Wang, Bo Qin, Ni Tang
Abstract
Diabetes commonly affects cancer patients. We investigated the influence of diabetes on breast cancer biology using a three-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.
Authors
Gatikrushna Panigrahi, Julián Candia, Tiffany H. Dorsey, Wei Tang, Yuuki Ohara, Jung S. Byun, Tsion Z. Minas, Amy L. Zhang, Anuoluwapo Ajao, Ashley Cellini, Harris G. Yfantis, Amy L. Flis, Dean Mann, Olga Ioffe, Xin Wei Wang, Huaitian Liu, Christopher A. Loffredo, Anna Maria Napoles, Stefan Ambs
Abstract
The histone demethylase JMJD2A/KDM4A facilitates prostate cancer development, yet how JMJD2A function is regulated has remained elusive. Here, we demonstrate that SET7/9-mediated methylation on 6 lysine residues modulated JMJD2A. Joint mutation of these lysine residues suppressed JMJD2A’s ability to stimulate the MMP1 matrix metallopeptidase promoter upon recruitment by the ETV1 transcription factor. Mutation of just 3 methylation sites (K505, K506, and K507) to arginine residues (3xR mutation) was sufficient to maximally reduce JMJD2A transcriptional activity and also decreased its binding to ETV1. Introduction of the 3xR mutation into DU145 prostate cancer cells reduced in vitro growth and invasion and also severely compromised tumorigenesis. Consistently, the 3xR genotype caused transcriptome changes related to cell proliferation and invasion pathways, including downregulation of MMP1 and the NPM3 nucleophosmin/nucleoplasmin gene. NPM3 downregulation phenocopied and its overexpression rescued, to a large degree, the 3xR mutation in DU145 cells, suggesting that NPM3 was a seminal downstream effector of methylated JMJD2A. Moreover, we found that NPM3 was overexpressed in prostate cancer and might be indicative of disease aggressiveness. SET7/9-mediated lysine methylation of JMJD2A may aggravate prostate tumorigenesis in a manner dependent on NPM3, implying that the SET7/9→JMJD2A→NPM3 axis could be targeted for therapy.
Authors
Ruicai Gu, Tae-Dong Kim, Hoogeun Song, Yuan Sui, Sook Shin, Sangphil Oh, Ralf Janknecht
Abstract
Despite being in the same pathway, mutations of KRAS and BRAF in colorectal carcinomas (CRCs) determine distinct progression courses. ZEB1 induces an epithelial-to-mesenchymal transition (EMT) and is associated with worse progression in most carcinomas. Using samples from patients with CRC, mouse models of KrasG12D and BrafV600E CRC, and a Zeb1-deficient mouse, we show that ZEB1 had opposite functions in KRAS- and BRAF-mutant CRCs. In KrasG12D CRCs, ZEB1 was correlated with a worse prognosis and a higher number of larger and undifferentiated (mesenchymal or EMT-like) tumors. Surprisingly, in BrafV600E CRC, ZEB1 was associated with better prognosis; fewer, smaller, and more differentiated (reduced EMT) primary tumors; and fewer metastases. ZEB1 was positively correlated in KRAS-mutant CRC cells and negatively in BRAF-mutant CRC cells with gene signatures for EMT, cell proliferation and survival, and ERK signaling. On a mechanistic level, ZEB1 knockdown in KRAS-mutant CRC cells increased apoptosis and reduced clonogenicity and anchorage-independent growth; the reverse occurred in BRAFV600E CRC cells. ZEB1 is associated with better prognosis and reduced EMT signature in patients harboring BRAF CRCs. These data suggest that ZEB1 can function as a tumor suppressor in BRAF-mutant CRCs, highlighting the importance of considering the KRAS/BRAF mutational background of CRCs in therapeutic strategies targeting ZEB1/EMT.
Authors
Ester Sánchez-Tilló, Leire Pedrosa, Ingrid Vila, Yongxu Chen, Balázs Győrffy, Lidia Sánchez-Moral, Laura Siles, Juan J. Lozano, Anna Esteve-Codina, Douglas S. Darling, Miriam Cuatrecasas, Antoni Castells, Joan Maurel, Antonio Postigo
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