Molecular Cancer Research最新文献

Glioblastoma (GBM) is amongst the deadliest types of cancers, with no resolutive cure currently available. GBM cell proliferation in the patient's brain is a complex phenomenon controlled by multiple mechanisms. The aim of this study was to determine whether the ionic fluxes controlling cell duplication could represent a target for GBM therapy. In this work, we combined multi-channel Ca2+ and Cl- imaging, optical tweezers, electrophysiology, and immunohistochemistry to describe the role of ion fluxes in mediating the cell volume changes that accompany mitosis of U87 GBM cells. We identified three main steps: (i) in round GBM cells undergoing mitosis, during the transition from anaphase to telophase and cytokinesis, large Ca2+ flares occur, reaching values of 0.5 to 1 μmol/L; (ii) these Ca2+ flares activate Ca2+-dependent Cl- channels, allowing the entry of Cl- ions; and (iii) to maintain osmotic balance, GBM cells swell to complete mitosis. This sequence of steps was validated by electrophysiological experiments showing that Cl- channels are activated either directly or indirectly by Ca2+, and by additional live-cell imaging experiments. Cl- channel blockers with different molecular structures, such as niflumic acid and carbenoxolone, blocked GBM replication by arresting GBM cells in a round configuration. These results describe the central role of Ca2+ flares and Cl- fluxes during mitosis and show that inhibition of Ca2+-activated Cl- channels blocks GBM replication, opening the way to new approaches for the clinical treatment of GBM. Implications: Our work identifies ionic fluxes occurring during cell division as targets for devising novel therapies for glioblastoma treatment.

Small cell lung cancer (SCLC) is an epithelial neuroendocrine form of lung cancer for which survival rates remain dismal and new therapeutic approaches are greatly needed. Key biological features of SCLC tumors include fast growth and widespread metastasis, as well as rapid resistance to treatment. Similar to pulmonary neuroendocrine cells, SCLC cells have traits of both hormone-producing cells and neurons. In this study, we specifically discuss the neuronal features of SCLC. We consider how neuronal G protein-coupled receptors and other neuronal molecules on the surface of SCLC cells can contribute to the growth of SCLC tumors and serve as therapeutic targets in SCLC. We also review recent evidence for the role of neuronal programs expressed by SCLC cells in the fast proliferation, migration, and metastasis of these cells. We further highlight how these neuronal programs may be particularly relevant for the development of brain metastases and how they can assist SCLC cells to functionally interact with neurons and astrocytes. A greater understanding of the molecular and cellular neuronal features of SCLC is likely to uncover new vulnerabilities in SCLC cells, which may help develop novel therapeutic approaches. More generally, the epithelial-to-neuronal transition observed during tumor progression in SCLC and other cancer types can contribute significantly to tumor development and response to therapy.

HBV-associated hepatocellular carcinoma (HCC) represents the prevalent form of HCC, with HBx protein being a crucial oncoprotein. Numerous members of the protein tyrosine phosphatase nonreceptor (PTPN) family have been confirmed to be significantly associated with the occurrence and progression of malignant tumors. Our group previously identified the involvement of PTPN13 in HCC. However, the roles of other PTPNs in HCC require further investigation. In this study, we found that PTPN18 expression was significantly downregulated within HCC tissues compared with adjacent nontumor and reference liver tissues. Functionally, PTPN18 exerted inhibitory effects on the proliferation, migration, invasion, and sphere-forming capability of HCC cells while concurrently promoting apoptotic processes. Through phospho-protein microarray screening followed by subsequent validation experiments, we identified that PTPN18 could activate the p53 signaling pathway and suppress the AKT/FOXO1 signaling cascade in HCC cells. Moreover, the HBx protein mediated the repression of PTPN18 expression by upregulating miR-128-3p. Collectively, our study unveiled the role of PTPN18 as a tumor suppressor in HBV-related HCC. Implications: Our findings revealed that PTPN18 might be a potential diagnostic and therapeutic target for HBV-related HCC.

There is tremendous need for improved prostate cancer models. Anatomically and developmentally, the mouse prostate differs from the human prostate and does not form tumors spontaneously. Genetically engineered mouse models lack the heterogeneity of human cancer and rarely establish metastatic growth. Human xenografts are an alternative but must rely on an immunocompromised host. Therefore, we generated prostate cancer murine xenograft models with an intact human immune system (huNOG and huNOG-EXL mice) to test whether humanizing tumor-immune interactions would improve modeling of metastatic prostate cancer and the impact of androgen receptor-targeted and immunotherapies. These mice maintain multiple human immune cell lineages, including functional human T-cells and myeloid cells. Implications: To the best of our knowledge, results illustrate the first model of human prostate cancer that has an intact human immune system, metastasizes to clinically relevant locations, responds appropriately to standard-of-care hormonal therapies, and can model both an immunosuppressive and checkpoint-inhibition responsive immune microenvironment.

Small-cell lung cancer (SCLC) accounts for nearly 15% of all lung cancers. Although patients respond to first-line therapy readily, rapid relapse is inevitable, with few treatment options in the second-line setting. Here, we describe SCLC cell lines harboring amplification of MYC and MYCN but not MYCL1 or non-amplified MYC cell lines exhibit superior sensitivity to treatment with the pan-BET bromodomain protein inhibitor mivebresib (ABBV075). Silencing MYC and MYCN partially rescued SCLC cell lines harboring these respective amplifications from the antiproliferative effects of mivebresib. Further characterization of genome-wide binding of MYC, MYCN, and MYCL1 uncovered unique enhancer and epigenetic preferences. Implications: Our study suggests that chromatin landscapes can establish cell states with unique gene expression programs, conveying sensitivity to epigenetic inhibitors such as mivebresib.

Targeting exhausted CD8+ T-cell (TEX)-induced aggravated cancer stem cells (CSC) holds immense therapeutic potential. In this regard, immunomodulation via Neem Leaf Glycoprotein (NLGP), a plant-derived glycoprotein immunomodulator is explored. Since former reports have proven immune dependent-tumor restriction of NLGP across multiple tumor models, we hypothesized that NLGP might reprogram and rectify TEX to target CSCs successfully. In this study, we report that NLGP's therapeutic administration significantly reduced TEX-associated CSC virulence in in vivo B16-F10 melanoma tumor model. A similar trend was observed in in vitro generated TEX and B16-F10/MCF7 coculture setups. NLGP rewired CSCs by downregulating clonogenicity, multidrug resistance phenotypes and PDL1, OCT4, and SOX2 expression. Cell cycle analysis revealed that NLGP educated-TEX efficiently pushed CSCs out of quiescent phase (G0G1) into synthesis phase (S), supported by hyper-phosphorylation of G0G1-S transitory cyclins and Rb proteins. This rendered quiescent CSCs susceptible to S-phase-targeting chemotherapeutic drugs like 5-fluorouracil (5FU). Consequently, combinatorial treatment of NLGP and 5FU brought optimal CSC-targeting efficiency with an increase in apoptotic bodies and proapoptotic BID expression. Notably a strong nephron-protective effect of NLGP was also observed, which prevented 5FU-associated toxicity. Furthermore, Dectin-1-mediated NLGP uptake and subsequent alteration of Notch1 and mTOR axis were deciphered as the involved signaling network. This observation unveiled Dectin-1 as a potent immunotherapeutic drug target to counter T-cell exhaustion. Cumulatively, NLGP immunotherapy alleviated exhausted CD8+ T-cell-induced CSC aggravation. Implications: Our study recommends that NLGP immunotherapy can be utilized to counter ramifications of T-cell exhaustion and to target therapy elusive aggressive CSCs without evoking toxicity.

Lung adenocarcinoma (LUAD) is the most prevalent histological type of lung cancer. Previous studies have reported that specific long noncoding RNAs (lncRNA) are involved in cancer development and progression. The phenotype and mechanism of ENST00000440028, named MSL3P1, an lncRNA referred to as a cancer-testis gene with potential roles in tumorigenesis and progression, have not been reported. MSL3P1 is overexpressed in LUAD tumor tissues, which is significantly associated with clinical characteristics, metastasis, and poor clinical prognosis. MSL3P1 promotes the metastasis of LUAD in vitro and in vivo. The enhancer reprogramming in LUAD tumor tissue is the major driver of the aberrant expression of MSL3P1. Mechanistically, owing to the competitive binding to CUL3 mRNA with ZFC3H1 protein (a protein involved in targeting polyadenylated RNA to exosomes and promoting the degradation of target mRNA), MSL3P1 can prevent the ZFC3H1-mediated RNA degradation of CUL3 mRNA and transport it to the cytoplasm. This activates the downstream epithelial-to-mesenchymal transition signaling pathway and promotes tumor invasion and metastasis. Implications: This study indicates that lncRNA MSL3P1 regulates CUL3 mRNA stability and promotes metastasis and holds potential as a prognostic biomarker and therapeutic target in LUAD.

Small cell lung cancer (SCLC) is an aggressive and lethal malignancy. Achaete-scute homolog 1 (ASCL1) is essential for the initiation of SCLC in mice and the development of pulmonary neuroendocrine cells (PNEC), which are the major cells of origin for SCLC. However, the regulatory mechanism of ASCL1 in SCLC remains elusive. Here, we found that ASCL1 expression gradually increases as the tumors grow in a mouse SCLC model, and is regulated by the cell cycle. Mechanistically, CDK2-CyclinA2 complex phosphorylates ASCL1, which results in increased proteasome-mediated ASCL1 protein degradation by E3 ubiquitin ligase HUWE1 during mitosis. TCF3 promotes the multisite phosphorylation of ASCL1 through the CDK2-CyclinA2 complex and the interaction between ASCL1 and TCF3 protects ASCL1 from degradation. The dissociation of TCF3 from ASCL1 during mitosis accelerates the degradation of ASCL1. In addition, chemotherapy drugs greatly reduce the transcription of ASCL1 in SCLC cells. Depletion of ASCL1 sensitizes SCLC cells to chemotherapy drugs. Together, our study demonstrates that ASCL1 is a cell-cycle-regulated protein and provides a theoretical basis for applying cell-cycle-related antitumor drugs in SCLC treatment. Implications:Our study revealed a novel regulatory mechanism of ASCL1 by cell cycle and chemotherapy drugs in SCLC. Treating patients with SCLC with a combination of ASCL1-targeting therapy and chemotherapy drugs could potentially be beneficial.

A key feature distinguishing high-grade glioma (HG) from low-grade glioma (LG) is the extensive neovascularization and endothelial hyperproliferation. Prior work has shown that tumor-associated vasculature from HG is molecularly and functionally distinct from normal brain vasculature and expresses higher levels of protumorigenic factors that promote glioma growth and progression. However, it remains unclear whether vessels from LG also express protumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of glioma-associated vascular cells (GVC) from IDH-mutant (mIDH) LG and IDH-wild-type (wIDH) HG and show that they exhibit significant molecular and functional differences. LG-GVC show enrichment of extracellular matrix-related gene sets and sensitivity to antiangiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and antiangiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo cotransplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, highly enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG are molecularly and functionally distinct and differentially regulate tumor growth. Implications: This study demonstrated that vascular cells from IDH-mutant LG and IDH-wild-type HG exhibit distinct molecular signatures and have differential effects on tumor growth via regulation of ASPN-TGFβ1-GPM6A signaling.