Dysregulation of glutaminase and glutamine synthetase in cancer Publication date: 28 December 2019 Source: Cancer Letters, Volume 467 Author(s): José M. Matés, José A. Campos-Sandoval, Juan de los Santos-Jiménez, Javier Márquez Abstract Besides fast glucose catabolism, many types of cancers are characterized by elevated glutamine consumption. Medical oncology pursuits to block specific pathways, mainly glycolysis and glutaminolysis, in tumor cells to arrest cancer development. This strategy frequently induces adaptive metabolic resistance that must be countered. Combination therapy is an anticancer synergistic tool to overcome both cancer growth and resistance mechanisms. Dysregulation of glutaminase and glutamine synthetase are key events that allow anabolic adaptation of tumors. Several specific drugs that inhibit metabolic enzymes dealing with glutamine metabolism have been able to eliminate some neoplasms. Targeting the tumor microenvironment can be also another essential factor to be taken into account when single or combined cancer metabolic therapy fails.

PLK1 and EGFR targeted nanoparticle as a radiation sensitizer for non-small cell lung cancer Publication date: 28 December 2019 Source: Cancer Letters, Volume 467 Author(s): Moataz Reda, Worapol Ngamcherdtrakul, Shenda Gu, Daniel S. Bejan, Natnaree Siriwon, Joe W. Gray, Wassana Yantasee Abstract Radiation sensitizers that can selectively act on cancer cells hold great promise to patients who receive radiation therapy. We developed a novel targeted therapy and radiation sensitizer for non-small cell lung cancer (NSCLC) based on cetuximab conjugated nanoparticle that targets epidermal growth factor receptor (EGFR) and delivers small interfering RNA (siRNA) against polo-like kinase 1 (PLK1). EGFR is overexpressed in 50% of lung cancer patients and a mediator of DNA repair, while PLK1 is a key mitotic regulator whose inhibition enhances radiation sensitivity. The nanoparticle construct (C-siPLK1-NP) effectively targets EGFR + NSCLC cells and reduces PLK1 expression, leading to G2/M arrest and cell death. Furthermore, we show a synergistic combination between C-siPLK1-NP and radiation, which was confirmed in vivo in A549 flank tumors. We also demonstrate the translational potential of C-siPLK1-NP as a systemic therapeutic in an orthotopic lung tumor model, where administration of C-siPLK1-NP reduced tumor growth and led to prolonged survival. Our findings demonstrate that C-siPLK1-NP is effective as a targeted therapy and as a potent radiation sensitizer for NSCLC. Potential application to other EGFR + cancer types such as colorectal and breast cancer is also demonstrated.

Antibiotic treatment ameliorates Ten-eleven translocation 2 (TET2) loss-of-function associated hematological malignancies Publication date: 28 December 2019 Source: Cancer Letters, Volume 467 Author(s): Hongxiang Zeng, Hailan He, Lei Guo, Jia Li, Minjung Lee, Wei Han, Anna G. Guzman, Shengbing Zang, Yubin Zhou, Xiaotian Zhang, Margaret A. Goodell, Katherine Y. King, Deqiang Sun, Yun Huang Abstract TET2 is among the most frequently mutated genes in hematological malignancies, as well as in healthy individuals with clonal hematopoiesis. Inflammatory stress is known to promote the expansion of Tet2-deficient hematopoietic stem cells, as well as the initiation of pre-leukemic conditions. Infection is one of the most frequent complications in hematological malignancies and antibiotics are commonly used to suppress infection-induced inflammation, but their application in TET2 mutation-associated cancers remained underexplored. In this study, we discovered that Tet2 depletion led to aberrant expansion of myeloid cells, which was correlated with elevated serum levels of pro-inflammatory cytokines at the pre-malignant stage. Antibiotics treatment suppressed the growth of Tet2-deficient myeloid and lymphoid tumor cells in vivo. Transcriptomic profiling further revealed significant changes in the expression of genes involved in the TNF-α signaling and other immunomodulatory pathways in antibiotics-treated tumor cells. Pharmacological inhibition of TNF-α signaling partially attenuated Tet2-deficient tumor cell growth in vivo. Therefore, our findings establish the feasibility of targeting pro-inflammatory pathways to curtail TET2 inactivation-associated hematological malignancies.

ATXN3 promotes breast cancer metastasis by deubiquitinating KLF4 Publication date: 28 December 2019 Source: Cancer Letters, Volume 467 Author(s): Haojing Zou, Hongyan Chen, Zhuan Zhou, Yong Wan, Zhihua Liu Abstract Krüppel-like factor 4 (KLF4) is an important transcription factor implicated in a variety of essential cellular processes. Aberrant KLF4 expression is closely related to tumourigenesis and tumour progression. The rapid turnover of the KLF4 protein indicates an important role for the posttranslational modifications (PTMs) of KLF4. To date, E3 ligases mediating KLF4 ubiquitination have been widely reported, yet the deubiquitinating mechanism of KLF4 remains largely unknown. We screened a library of 65 deubiquitinating enzymes and identified ATXN3 as a deubiquitinating enzyme of KLF4. Subsequent immunoprecipitation assays confirmed that ATXN3 bound to KLF4, mediating the deubiquitination and stabilization of KLF4 protein levels. Furthermore, we demonstrated that ATXN3 promoted breast cancer cell metastasis via KLF4 in vitro and in vivo. Finally, the protein expression analysis of human breast cancer specimens demonstrated that ATXN3 significantly correlated with KLF4. High ATXN3/KLF4 expression was associated with a poor prognosis in breast cancer patients. Collectively, we identified ATXN3 as a novel deubiquitinating enzyme of KLF4, providing a new explanation for breast cancer metastasis, and proposed ATXN3 as a potential target for breast cancer metastasis treatment.

Sex disparities in cancer Publication date: 1 December 2019 Source: Cancer Letters, Volume 466 Author(s): Yizhi Zhu, Xiaoyan Shao, Xueyan Wang, Lingxiang Liu, Han Liang Abstract Sex is a key biological factor affecting the development of many cancer types. There are considerable differences between male and female subpopulations in terms of cancer incidence, prognosis and mortality. Recent studies have extensively characterized the sex-biased molecular changes in cancer patients. Further efforts should be made to develop sex-specific cancer prevention and therapeutic strategies.

Noninvasive imaging in cancer immunotherapy: The way to precision medicine Publication date: 1 December 2019 Source: Cancer Letters, Volume 466 Author(s): Yang Du, Yafei Qi, Zhengyu Jin, Jie Tian Abstract Molecular medicine requires a more precise treatment directed at molecular aberrations detected in tumors on an individual patient level. Immunotherapies empower the body's own immune system to confront tumor cells; however, their efficacy is often affected by tumor heterogeneity. Numerous noninvasive imaging techniques are available to monitor changes in tumor function reflecting therapeutic response, including immunotherapy, and to realize personalized response evaluation. For immunotherapy, strategies for using noninvasive imaging as a prognostic biomarker to identify patients who could benefit from targeted immunotherapy and predict early responders/nonresponders may ultimately lead to improved clinical management, individualized therapy regimens, and better prediction of patient outcomes. Herein, we summarize the recent progress in noninvasive imaging of immunotherapeutic targets such as immune cells, immune checkpoint inhibitors, immune vaccines, and T-cell therapy with chimeric antigen receptor, and review the clinical application of noninvasive imaging in immunotherapy. Finally, we describe the application of multimodal/multispectral imaging and radiomics, which may offer future direction for precision imaging in immunotherapy. With further progress of noninvasive imaging, guiding cancer immunotherapy into the era of precision medicine would be a promising option.

Inhibition of hydrogen sulfide synthesis reverses acquired resistance to 5-FU through miR-215-5p-EREG/TYMS axis in colon cancer cells Publication date: 1 December 2019 Source: Cancer Letters, Volume 466 Author(s): Shanwen Chen, Taohua Yue, Zhihao Huang, Jing Zhu, Dingfang Bu, Xin Wang, Yisheng Pan, Yucun Liu, Pengyuan Wang Abstract Acquired resistance to 5-fluorouracil (5-FU) is a major barrier to benefit from chemotherapy in colon cancer patients. Hydrogen sulfide (H2S), mainly produced by cystathionine-β-synthase (CBS), has been reported to promote the proliferation and migration of colon cancer cells. In this study, the effect of inhibiting H2S synthesis on the sensitivity of colon cancer cell lines to 5-FU was investigated. Increased expression of CBS was validated in online database and tissue microarrays. Inhibiting H2S synthesis significantly sensitized colon cancer cell lines to 5-FU both in vitro and in vivo. Decreasing H2S synthesis utilizing shRNA lentiviruses significantly reversed the acquired resistance to 5-FU. MicroRNA sequencing was performed and miR-215-5p was revealed as one of the miRNAs with most significantly altered expression levels after CBS knock down. Epiregulin (EREG) and thymidylate synthetase (TYMS) were predicted to be potential targets of miR-215-5p. Decreasing H2S synthesis significantly decreased the expression of EREG and TYMS. These results demonstrate that inhibiting H2S synthesis can reverse the acquired resistance to 5-FU in colon cancer cells.

NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis Publication date: 1 December 2019 Source: Cancer Letters, Volume 466 Author(s): Haoyan Guo, Jiaqian Xu, Quan Zheng, Jianli He, Wei Zhou, Kezhou Wang, Xian Huang, Qiuju Fan, Jiao Ma, Jinke Cheng, Wenhan Mei, Rong Xing, Rong Cai Abstract Nuclear factor erythroid-2 related factor 2 (NRF2) is a pivotal transcription factor that maintains cellular redox homeostasis and facilitates the development of malignant tumor phenotypes. At the molecular level, NRF2 promotes de novo serine synthesis and SUMOylation affects its function. Our results indicated that the SUMO1 acceptor site of NRF2 is the conserved lysine residue 110 (K110), and that NRF2 SUMOylation deficiency inhibited tumorigenesis in hepatocellular carcinoma (HCC). Mechanistically, NRF2 SUMOylation promoted de novo serine synthesis in HCC by enhancing the clearance of intracellular reactive oxygen species (ROS) and up-regulating phosphoglycerate dehydrogenase (PHGDH). More importantly, serine starvation increased the level of NRF2 SUMOylation, leading to sustained HCC growth. Collectively, our results indicate the presence of a novel NRF2 SUMOylation-mediated signaling process that maintains HCC tumorigenesis in normal conditions and in response to metabolic stress.

Dual-targeting of EGFR and Neuropilin-1 attenuates resistance to EGFR-targeted antibody therapy in KRAS-mutant non-small cell lung cancer Publication date: 1 December 2019 Source: Cancer Letters, Volume 466 Author(s): Ye-Jin Kim, Du-San Baek, Seyoung Lee, Daechan Park, Han Na Kang, Byoung Chul Cho, Yong-Sung Kim Abstract The therapeutic targeting of oncogenic KRAS mutant-harboring (KRASMUT) non-small cell lung cancer (NSCLC) is an urgent unmet need in cancer therapy. Although NSCLC is often driven by epidermal growth factor receptor (EGFR) overexpression and/or mutations, no EGFR-targeted therapy is clinically available for KRASMUT NSCLC. In this study, we show that integrin β3 expression is associated with the intrinsic resistance of KRASMUT NSCLCs to the anti-EGFR antibody cetuximab. Further analyses identified an integrin β3-mediated ternary complex comprising NRP1–integrin β3–KRASMUT and its downstream signaling of PI3K-Akt and RalB-TBK1 as a primary resistance mechanism of KRASMUT NSCLC to cetuximab treatment. Importantly, we demonstrate that the EGFR/NRP1 dual-targeting bispecific antibody, Ctx-TPP11, attenuates the downstream signaling driven by the ternary complex via the cellular co-internalization and degradation of the NRP1-coupled complex, resulting in the alleviation of cetuximab resistance in KRASMUT NSCLCs in vitro and in vivo, including patient-derived xenograft mouse models. Our study shows that the dual-targeting of EGFR and NRP1 with a bispecific antibody might be an effective therapeutic strategy for KRASMUT NSCLC.

Glioblastoma extracellular vesicles induce the tumour-promoting transformation of neural stem cells Publication date: 1 December 2019 Source: Cancer Letters, Volume 466 Author(s): Jian Wang, Jialin Liu, Guochen Sun, Hengxing Meng, Jiayin Wang, Yunqian Guan, Yiheng Yin, Zhenyu Zhao, Xiying Dong, Shangjiong Yin, Hongwei Li, Yuefei Cheng, Hao Wu, Anhua Wu, Xinguang Yu, Ling Chen Abstract Recurrent glioblastomas are frequently found near subventricular zone (SVZ) areas of the brain where neural stem cells (NSCs) reside, and glioblastoma-derived extracellular vesicles (EVs) are reported to play important roles in tumour micro-environment, but the details are not clear. Here, we investigated the possibility that NSCs are involved in glioblastoma relapse mediated by glioblastoma-derived EVs. We studied changes to NSCs by adding glioblastoma-derived EVs into a culture system of NSCs, and found that NSCs differentiated into a type of tumour-promoting cell. These transformed cells had distinguished proliferation activity, a high migration rate, and clone-forming ability revealed by CCK-8, wound healing and soft agar clone formation assays, respectively. In vivo assays indicated that these cells could accelerate tumour formation by Ln229 cells in nude mice. Moreover, to explore the mechanisms underlying NSC transformation, single cell transcriptome sequencing was performed; our results suggest that several key genes such as S100B, CXCL14, EFEMP1, SCRG1, GLIPR1, HMGA1 and CD44 and dysregulated signalling may be important for the transformation of NSCs. It is also indicated that NSCs may be involved in glioblastoma recurrence through EV release by glioblastoma in this work. This could help to illuminate the mechanism of glioblastoma relapse, which occurs in a brief period after surgical excision, and contribute to finding new ways to treat this disease.