bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒03‒01
thirty papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Cell Biol. 2020 Feb 24.
    Montagner M, Bhome R, Hooper S, Chakravarty P, Qin X, Sufi J, Bhargava A, Ratcliffe CDH, Naito Y, Pocaterra A, Tape CJ, Sahai E.
      The process of metastasis is complex1. In breast cancer, there are frequently long time intervals between cells leaving the primary tumour and growth of overt metastases2,3. Reasons for disease indolence and subsequent transition back to aggressive growth include interactions with myeloid and fibroblastic cells in the tumour microenvironment and ongoing immune surveillance4-6. However, the signals that cause actively growing cells to enter an indolent state, thereby enabling them to survive for extended periods of time, are not well understood. Here we reveal how the behaviour of indolent breast cancer cells in the lung is determined by their interactions with alveolar epithelial cells, in particular alveolar type 1 cells. This promotes the formation of fibronectin fibrils by indolent cells that drive integrin-dependent pro-survival signals. Combined in vivo RNA sequencing and drop-out screening identified secreted frizzled-related protein 2 (SFRP2) as a key mediator of this interaction. Sfrp2 is induced in breast cancer cells by signals from lung epithelial cells and promotes fibronectin fibril formation and survival, whereas blockade of Sfrp2 expression reduces the burden of indolent disease.
  2. Nat Commun. 2020 Feb 28. 11(1): 1121
    Jayashankar V, Edinger AL.
      Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty acids and nucleotides for biosynthesis, conferring resistance to therapies targeting anabolic pathways. Indeed, necrotic cell debris allow macropinocytic breast and prostate cancer cells to proliferate, despite fatty acid synthase inhibition. Standard therapies such as gemcitabine, 5-fluorouracil (5-FU), doxorubicin and gamma-irradiation directly or indirectly target nucleotide biosynthesis, creating stress that is relieved by scavenged nucleotides. Strikingly, necrotic debris also render macropinocytic, but not non-macropinocytic, pancreas and breast cancer cells resistant to these treatments. Selective, genetic inhibition of macropinocytosis confirms that necrocytosis both supports tumor growth and limits the effectiveness of 5-FU in vivo. Therefore, this study establishes necrocytosis as a mechanism for drug resistance.
  3. Exp Biol Med (Maywood). 2020 Feb 26. 1535370220909309
    Shen YA, Pan SC, Chu I, Lai RY, Wei YH.
    Keywords:  Cancer stem cell; HIF; Myc; metabolic reprogramming; p53
  4. Nature. 2020 Feb 26.
    Lu Z, Zou J, Li S, Topper MJ, Tao Y, Zhang H, Jiao X, Xie W, Kong X, Vaz M, Li H, Cai Y, Xia L, Huang P, Rodgers K, Lee B, Riemer JB, Day CP, Yen RC, Cui Y, Wang Y, Wang Y, Zhang W, Easwaran H, Hulbert A, Kim K, Juergens RA, Yang SC, Battafarano RJ, Bush EL, Broderick SR, Cattaneo SM, Brahmer JR, Rudin CM, Wrangle J, Mei Y, Kim YJ, Zhang B, Wang KK, Forde PM, Margolick JB, Nelkin BD, Zahnow CA, Pardoll DM, Housseau F, Baylin SB, Shen L, Brock MV.
      Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.
  5. J Exp Med. 2020 Apr 06. pii: e20192312. [Epub ahead of print]217(4):
    Ma X.
      The work by Etzerodt et al. in this issue of JEM ( identifies a distinct omentum-resident macrophage population of embryonic origin and demonstrates that these cells provide a niche for ovarian cancer metastasis and cancer stemness. This research opens up for many questions and therapeutic prospects.
  6. Med Hypotheses. 2020 Feb 19. pii: S0306-9877(19)31325-8. [Epub ahead of print]140 109639
    Shankar E, Franco D, Iqbal O, El-Hayek V, Gupta S.
      Development of resistance to anti-androgen therapy limits the usefulness of second-generation androgen receptor (AR) antagonists including enzalutamide and abiraterone in castration resistant prostate cancer (CRPC) patients. Recent genomic studies reveal that AR-regulated genes contribute to CRPC emergence. Several reasons for the development of resistance towards anti-androgens have been hypothesized, including intracellular testosterone production, androgen overexpression, somatic mutations of AR resulting in a gain of function, constitutive activation of AR splice variants, imbalance in AR regulators, and bypass of AR in CRPC progression. Recent findings suggest that epigenetic alterations are involved in the deregulation of AR signaling. Overexpression of enhancer of zeste homolog 2 (EZH2), the enzymatic member of the polycomb repressor complex PRC2, has emerged as a key activator of AR in CRPC. Studies indicate that overabundance of EZH2 in localized prostate tumors increases the risk of biochemical recurrence after surgery, as it activates AR by enhancing methylation, resulting in the suppression of tumor suppressor genes and activation of oncogenes. This apparent association between EZH2 and AR in activating target genes by cooperative recruitment might play a critical role in the emergence of CRPC. Our hypothesis is that combination treatment targeting EZH2 and AR may be a novel efficacious therapeutic regime for the treatment of castrate resistant prostate cancer, and we propose to investigate this possibility.
    Keywords:  Androgen receptor; Castration resistant prostate cancer; Enhancer of zeste homolog 2; Polycomb repressor complex
  7. Mol Cancer. 2020 Feb 26. 19(1): 38
    Liang W, Lin Z, Du C, Qiu D, Zhang Q.
      Despite their small numbers, cancer stem cells play a central role in driving cancer cell growth, chemotherapeutic resistance, and distal metastasis. Previous studies mainly focused on how DNA or histone modification determines cell fate in cancer. However, it is still largely unknown how RNA modifications orchestrate cancer cell fate decisions. More than 170 distinct RNA modifications have been identified in the RNA world, while only a few RNA base modifications have been found in mRNA. Growing evidence indicates that three mRNA modifications, inosine, 5-methylcytosine, and N6-methyladenosine, are essential for the regulation of spatiotemporal gene expression during cancer stem cell fate transition. Furthermore, transcriptome-wide mapping has found that the aberrant deposition of mRNA modification, which can disrupt the gene regulatory network and lead to uncontrollable cancer cell growth, is widespread across different cancers. In this review, we try to summarize the recent advances of these three mRNA modifications in maintaining the stemness of cancer stem cells and discuss the underlying molecular mechanisms, which will shed light on the development of novel therapeutic approaches for eradicating cancer stem cells.
    Keywords:  5-methylcytosine; A-to-I editing; Cancer stem cells; N6-methyladenosine; RNA modification
  8. Cancer Cell. 2020 Feb 14. pii: S1535-6108(20)30050-7. [Epub ahead of print]
    McGrail DJ, Garnett J, Yin J, Dai H, Shih DJH, Lam TNA, Li Y, Sun C, Li Y, Schmandt R, Wu JY, Hu L, Liang Y, Peng G, Jonasch E, Menter D, Yates MS, Kopetz S, Lu KH, Broaddus R, Mills GB, Sahni N, Lin SY.
      Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.
    Keywords:  colorectal cancer (COAD); endometrial cancer (UCEC); immunotherapy; microsatellite instability (MSI); mismatch repair (MMR); neddylation; protein degredation; protein homeostasis
  9. Oncogene. 2020 Feb 27.
    Kasiri S, Chen B, Wilson AN, Reczek A, Mazambani S, Gadhvi J, Noel E, Marriam U, Mino B, Lu W, Girard L, Solis LM, Luby-Phelps K, Bishop J, Kim JW, Kim J.
      Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. Here, we demonstrate that the canonical Hh signaling pathway is activated in lung stroma by Hh ligands secreted from transformed lung epithelia. Genetic deletion of Shh, the primary Hh ligand expressed in the lung, in KrasG12D/+;Trp53fl/fl autochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH, another Hh ligand, by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, rather than SHH, activates the pathway in stroma to drive its tumor suppressive effects-a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased DNA damage suggestive of reactive oxygen species (ROS) activity. Treatment of KrasG12D/+;Trp53fl/fl mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor DNA damage, inhibited tumor growth and prolonged mouse survival. Thus, IHH induces stromal activation of the canonical Hh signaling pathway to suppress tumor growth and metastases, in part, by limiting ROS activity.
  10. J Cell Biochem. 2020 Feb 26.
    Fang J, Huang C, Ke J, Li J, Zhang W, Xue H, Chen J.
      Breast cancer is a common malignant tumor suffered predominantly by women worldwide, which results in serious levels of morbidity and mortality. To control the effects of the cancer, it is critically important to elucidate the pathophysiological processes by which it occurs and develops. Reports have demonstrated that long noncoding RNAs perform a critical role in the development and metastasis of cancers. The lncRNA TTN-AS1 is considered carcinogenic. Nevertheless, the importance and biological functions of TTN-AS1 in breast cancer require greater exploration. In the current paper, we observed that TTN-AS1 expression was significantly upregulated in breast cancer tissues/cells compared with those that are healthy. TTN-AS1 enhanced the proliferation, migration, invasion, and epithelial-mesenchymal transformation of breast cancer cells. Furthermore, a direct target of TTN-AS1, miR-139-5p was negatively regulated. In addition, zinc finger E-box binding homeobox 1 (ZEB1) is an important nuclear transcription factor, the expression of which is increased in multiple tumors. Here, we also found that ZEB1 is a target of miR-139-5p, of which TTN-AS1 could regulate the expression through competition with miR-139-5p. That is, TTN-AS1 promoted proliferation and invasion of breast cancer cells by interaction with the miR-139-5p/ZEB1 axis. In conclusion, the present study aimed to illustrate the significance of TTN-AS1 in breast cancer metastasis and contribute to potentially innovative strategies for its treatment.
    Keywords:  TTN-AS1; breast cancer; epithelial-mesenchymal transition; lncRNA; miR-139-5p
  11. Biomolecules. 2020 Feb 19. pii: E337. [Epub ahead of print]10(2):
    Zarrer J, Haider MT, Smit DJ, Taipaleenmäki H.
      Bone is the most common metastatic site in breast cancer. Upon arrival to the bone, disseminated tumor cells can undergo a period of dormancy but often eventually grow and hijack the bone microenvironment. The bone marrow microenvironment consists of multiple cell types including the bone cells, adipocytes, endothelial cells, and nerve cells that all have crucial functions in the maintenance of bone homeostasis. Tumor cells severely disturb the tightly controlled cellular and molecular interactions in the bone marrow fueling their own survival and growth. While the role of bone resorbing osteoclasts in breast cancer bone metastases is well established, the function of other bone cells, as well as adipocytes, endothelial cells, and nerve cells is less understood. In this review, we discuss the composition of the physiological bone microenvironment and how the presence of tumor cells influences the microenvironment, creating a pathological crosstalk between the cells. A better understanding of the cellular and molecular events that occur in the metastatic bone microenvironment could facilitate the identification of novel cellular targets to treat this devastating disease.
    Keywords:  adipocyte; bone metastases; bone microenvironment; breast cancer; hypoxia; nerve cells; osteoblast; osteoclast; osteocyte; vasculature
  12. Cancer. 2020 Feb 26.
    Yalniz FF, Patel KP, Bashir Q, Marin D, Ahmed S, Alousi AM, Chen J, Ciurea SO, Rezvani K, Popat UR, Shpall EJ, Champlin RE, Oran B.
      BACKGROUND: Despite the well-defined role of minimal residual disease (MRD) monitoring by real-time quantitative polymerase chain reaction (RT-PCR) for RUNX1/RUNX1T1 and CBFB-MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT).METHODS: Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis.
    RESULTS: MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3-year overall survival (OS) and leukemia-free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD-negative patients had 3-year OS and LFS rates of 100% and 100%, respectively. Thirty-five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT-PCR, and 14 (40%) were MRDpos. The presence of MRD by RT-PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2).
    CONCLUSIONS: Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT-PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials.
    Keywords:  acute myeloid leukemia; allogeneic stem cell transplantation; core binding factor leukemia; measurable residual disease; real-time quantitative polymerase chain reaction (RT-PCR)
  13. Cancers (Basel). 2020 Feb 26. pii: E533. [Epub ahead of print]12(3):
    Leung MH, Tsoi H, Gong C, Man EP, Zona S, Yao S, Lam EW, Khoo US.
      Breast cancer is the most common type of female cancer. Reactive oxygen species (ROS) are vital in regulating signaling pathways that control cell survival and cell proliferation. Chemotherapeutic drugs such as anthracyclines induce cell death via ROS induction. Chemoresistance development is associated with adaptive response to oxidative stress. NRF2 is the main regulator of cytoprotective response to oxidative stress. NRF2 can enhance cell growth, antioxidant expression, and chemoresistance by providing growth advantage for malignant cells. Previously, we identified BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, which can robustly predict tamoxifen resistance in primary breast cancer. In this study, we found that BQ was overexpressed in epirubicin-resistant cells and demonstrated that BQ overexpression could reduce the levels of epirubicin-induced ROS and confer epirubicin resistance. In vivo analysis using tissue microarray of primary breast cancer showed direct correlation between BQ expression and chemoresistance. In vitro experiments showed BQ could modulate NRF2 transcriptional activity and upregulate antioxidants. Luciferase reporter assays showed that although NCOR2 repressed the transcriptional activity of NRF2, the presence of BQ reduced this repressive activity. Co-immunoprecipitation confirmed that NCOR2 could bind to NRF2 and that this interaction was compromised by BQ overexpression, leading to increased transcriptional activity in NRF2. Our findings suggest BQ can regulate the NRF2 signaling pathway via interference with NCOR2 suppressive activity and reveals a novel role for BQ as a modulator of chemoresistance in breast cancer.
    Keywords:  NCOR2; NRF2; breast cancer; chemoresistance; splice variant BQ
  14. Arch Med Res. 2020 Feb 25. pii: S0188-4409(19)30620-4. [Epub ahead of print]
    Zohny SF, Zamzami MA, Al-Malki AL, Trabulsi NH.
      BACKGROUND: The role of Notch signaling dysregulation in causing metastatic breast cancer is not yet elucidated, therefore, this study aimed to investigate the expression of DLL4 and JAG1 in metastatic breast cancer. Moreover, we examined the possible association between clinicopathological features and studied parameters.DESIGN AND METHODS: A total of 90 patients with invasive ductal breast carcinomas (52 non-metastatic and 38 metastatic) were enrolled in the current study. Furthermore, there were 42 patients with benign breast diseases. The mRNA and protein expression of DLL4 and JAG1 were analyzed by RT-PCR and ELISA, respectively in breast cell lysates.
    RESULTS: The mRNA and protein expression of DLL4 and JAG1 were obviously higher in patients with breast cancer compared to patients with benign breast diseases and in metastatic versus non-metastatic breast cancer. A significant positive correlation was declared between DLL4 and JAG1 at both mRNA and protein levels in metastatic and localized breast cancer patients. Highly expressed mRNA and protein of DLL4 and JAG1 were associated with late tumor stages; moreover, upregulation of mRNA and protein of JAG1 was correlated with poorly differentiated tumors.
    CONCLUSION: Our data emphasize that overexpression of DLL4 and JAG1 could predict the development of distant metastasis in breast cancer patients.
    Keywords:  Breast cancer; Clinicopathological features; DLL4; JAG1
  15. Life Sci. 2020 Feb 25. pii: S0024-3205(20)30217-4. [Epub ahead of print] 117469
    Chen J, Li N, Liu B, Ling J, Yang W, Pang X, Li T.
      AIMS: Histone deacetylases inhibitors have shown favorable antitumor activity in clinical investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying molecular mechanisms.MAIN METHODS: MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the molecular mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 subcutaneous tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects.
    KEY FINDINGS: Our results demonstrated that SB939 at 0.5-1 μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models.
    SIGNIFICANCE: Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.
    Keywords:  Breast cancer; EMT; HDACs; SB939; Tumor metastasis
  16. Int J Mol Sci. 2020 Feb 20. pii: E1427. [Epub ahead of print]21(4):
    Saleh T, Tyutyunyk-Massey L, H Patel N, K Cudjoe E, Alotaibi M, A Gewirtz D.
      Autophagy and senescence, predominant responses that may dictate cell fate after chemotherapy or radiation, often occur in tandem. Cells in states of senescence and/or autophagy are frequently growth arrested. We have previously reported that tumor cells induced into senescence by therapy can re-emerge from the growth-arrested state, a phenomenon termed proliferative recovery. The current work shows that, while tumor cells collaterally induced into senescence and autophagy by etoposide, doxorubicin, or radiation undergo proliferative recovery, neither pharmacological nor genetic inhibition of early autophagy alter the extent of senescence or the ability of cells to recover from senescence. These findings confirm and extend our previous observations, essentially dissociating senescence from autophagy, and further indicate that re-emergence from senescence does not appear to be facilitated by or dependent on autophagy. Our results also provide additional evidence for the promotion of the non-protective form of autophagy by both chemotherapeutic drugs and radiation, which may complicate current efforts to inhibit autophagy for therapeutic benefit.
    Keywords:  autophagy; cancer; chemotherapy; proliferative recovery; radiotherapy; senescence
  17. Future Med Chem. 2020 Feb 26.
    Stefan SM, Jansson PJ, Kalinowski DS, Anjum R, Dharmasivam M, Richardson DR.
    Keywords:  ABCB1 lysosomes; P-gp; P-gp endocytosis; lysosomal P-gp activity; lysosomal membrane permeabilization; redox-active (-cycling) thiosemicarbazone complexes; thiosemicarbazone; thiosemicarbazone ionization
  18. Dev Cell. 2020 Feb 24. pii: S1534-5807(20)30066-6. [Epub ahead of print]52(4): 413-428.e6
    Vasudevan A, Baruah PS, Smith JC, Wang Z, Sayles NM, Andrews P, Kendall J, Leu J, Chunduri NK, Levy D, Wigler M, Storchová Z, Sheltzer JM.
      High levels of cancer aneuploidy are frequently associated with poor prognosis. To examine the relationship between aneuploidy and cancer progression, we analyzed a series of congenic cell lines that harbor single extra chromosomes. We found that across 13 different trisomic cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, we discovered that chromosomal instability activates cGAS/STING signaling but strongly suppresses invasiveness. By analyzing patient copy-number data, we demonstrate that specific aneuploidies are associated with distinct outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different aneuploidies can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, thereby linking genomic plasticity, phenotypic plasticity, and metastasis.
    Keywords:  EMT; aneuploidy; cGAS/STING; chromosome missegregation; copy number variation; metastasis
  19. Biology (Basel). 2020 Feb 22. pii: E39. [Epub ahead of print]9(2):
    Gruet M, Cotton D, Coveney C, Boocock DJ, Wagner S, Komorowski L, Rees RC, Pockley AG, Garner AC, Wallis JD, Miles AK, Powe DG.
      Metastasis is associated with poor prognosis in breast cancer. Although some studies suggest beta-blockers increase survival by delaying metastasis, others have been discordant. This study provides both insights into the anomalous findings and identifies potential biomarkers that may be treatment targets. Cell line models of basal-type and oestrogen receptor-positive breast cancer were profiled for basal levels of adrenoceptor gene/protein expression, and β2-adrenoceptor mediated cell behaviour including migration, invasion, adhesion, and survival in response to adrenoceptor agonist/antagonist treatment. Protein profiling and histology identified biomarkers and drug targets. Baseline levels of adrenoceptor gene expression are higher in basal-type rather than oestrogen receptor-positive cancer cells. Norepinephrine (NE) treatment increased invasive capacity in all cell lines but did not increase proliferation/survival. Protein profiling revealed the upregulation of the pro-metastatic gene Ly6/PLAUR Domain-Containing Protein 3 (LYPD3) in norepinephrine-treated MDA-MB-468 cells. Histology confirmed selective LYPD3 expression in primary and metastatic breast tumour samples. These findings demonstrate that basal-type cancer cells show a more aggressive adrenoceptor-β2-activated phenotype in the resting and stimulated state, which is attenuated by adrenoceptor-β2 inhibition. This study also highlights the first association between ADRβ2 signalling and LYPD3; its knockdown significantly reduced the basal and norepinephrine-induced activity of MCF-7 cells in vitro. The regulation of ADRβ2 signalling by LYPD3 and its metastasis promoting activities, reveal LYPD3 as a promising therapeutic target in the treatment of breast and other cancers.
    Keywords:  LYPD3; beta-blockers; breast cancer; β2-adrenoceptor
  20. Mol Cell Endocrinol. 2020 Feb 19. pii: S0303-7207(20)30062-9. [Epub ahead of print]506 110762
    Yu T, Cheng H, Ding Z, Wang Z, Zhou L, Zhao P, Tan S, Xu X, Huang X, Liu M, Peng M, Qiu YA.
      Rescue chemotherapy is usually the preferred treatment for patients with advanced estrogen receptor-positive (ER+) breast cancer with endocrinotherapy resistance. However, these patients often simultaneously show a poor response to cytotoxic drugs, and thus the detailed mechanism of this resistance needs to be further investigated. Our previous research indicated that the G-protein-coupled estrogen receptor (GPER) is a novel mediator of the development of multidrug resistance, including resistance to both endocrinotherapy and chemotherapy, and ATP binding cassette subfamily G member 2 (ABCG2) has been identified as an engine that confers cancer cells with chemoresistance by expelling xenobiotics and chemotherapeutics. Here, we are the first to show that the expression levels of GPER and ABCG2 are markedly increased in tamoxifen-resistant ER + metastases compared to the corresponding primary tumors. A plasma membrane expression pattern of GPER and ABCG2 was observed in patients with metastases. Furthermore, both ER modulator tamoxifen, GPER-specific agonist G1 and pure ER antagonist ICI 182,780 significantly enhanced ABCG2 expression in tamoxifen-resistant breast cancer cells (MCF-7R) but not in tamoxifen-sensitive cells (MCF-7). The activated downstream GPER/EGFR/ERK and GPER/EGFR/AKT signaling pathways were responsible for regulating the expression and cell membrane localization of ABCG2, respectively, in MCF-7R cells. Interestingly, the above phenomenon could be alleviated by inhibitors of both the indicated signaling pathways and by knockdown of GPER in MCF-7R cells. More importantly, the tamoxifen-induced GPER/ABCG2 signaling axis was shown to play a pivotal role in the development of chemotherapy (doxorubicin) resistance both in vitro and in vivo. The clinical data further revealed that tamoxifen-resistant patients with high GPER/ABCG2 signaling activation had poor progression-free survival (PFS) when given rescue anthracycline chemotherapy. Therefore, our data provide novel insights into GPER-mediated chemoresistance and provide a rationale for the GPER/ABCG2 signaling axis being a promising target for reversing chemoresistance in patients with advanced ER + tamoxifen-resistant breast cancer.
    Keywords:  ABCG2; Breast cancer; Chemotherapeutic resistance; GPER
  21. Mol Cancer. 2020 Feb 27. 19(1): 43
    Zhang H, Deng T, Liu R, Ning T, Yang H, Liu D, Zhang Q, Lin D, Ge S, Bai M, Wang X, Zhang L, Li H, Yang Y, Ji Z, Wang H, Ying G, Ba Y.
      BACKGROUND: Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic.METHODS: Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential.
    RESULTS: Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity.
    CONCLUSIONS: The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC.
    Keywords:  Cancer-associated fibroblasts; Exosomes; Ferroptosis; GC; miR-522
  22. Sci Transl Med. 2020 Feb 26. pii: eaay7522. [Epub ahead of print]12(532):
    Huang M, Zhang D, Wu JY, Xing K, Yeo E, Li C, Zhang L, Holland E, Yao L, Qin L, Binder ZA, O'Rourke DM, Brem S, Koumenis C, Gong Y, Fan Y.
      Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces β-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.
  23. Drug Dev Res. 2020 Feb 25.
    Xiao F, Ouyang B, Zou J, Yang Y, Yi L, Yan H.
      OBJECTIVE: To study the relationship between TRIM14 expression and chemotherapy resistance of gastric cancer (GC) cells.METHODS: The expression of TRIM14 in 5-fluorouracil (5-FU)- and oxaliplation (L-OHP)-resistant GC tissues and cells were determined by qRT-PCR and western blotting. PcDNA3.1-TRIM14 and shRNA-TRIM14 vector were transfected to 5-FU-resistant GC cells (SGC7901/5-FU), and the proliferation and apoptosis of cells were measured. Animal experiments on 5-FU-resistant GC mice were performed to study the effect of TRIM14 expression on tumor size and weight, GC cell migration, and proliferation. pcDNA3.1-MK-3903 plasmid was transfected to SGC7901/5-FU cells with TRIM14 silence. The cell proliferation and apoptosis were determined. The protein expressions of Trim14, LC3, and BECLIN1 were measured by western blotting.
    RESULTS: TRIM14 was significantly upregulated in 5-FU- and L-OHP-resistant GC tissues and cells. The overexpression of TRIM14 promoted the proliferation and autophagy of SGC7901/5-FU cells, and inhibited the apoptosis. Moreover, in vivo experiment verified that the silence of TRIM14 reduced the tumor size and weight, and inhibited the migration and proliferation of GC cells in 5-FU-resistant GC mice. The overexpression of MK-3903 reversed the inhibiting role of TRIM14 knockout on the proliferation and autophagy of SGC7901/5-FU cells.
    CONCLUSION: TRIM14 promoted chemotherapy resistance of GC cells by regulating AMPK/mTOR pathway, and may be a new biomarker for treating GC.
    Keywords:  AMPK/mTOR; TRIM14; chemotherapy resistance; gastric cancer
  24. Nat Commun. 2020 Feb 28. 11(1): 1141
    Wang X, Qin G, Liang X, Wang W, Wang Z, Liao D, Zhong L, Zhang R, Zeng YX, Wu Y, Kang T.
      Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis.
  25. Cell Rep. 2020 Feb 25. pii: S2211-1247(20)30105-4. [Epub ahead of print]30(8): 2729-2742.e4
    Michalopoulou E, Auciello FR, Bulusu V, Strachan D, Campbell AD, Tait-Mulder J, Karim SA, Morton JP, Sansom OJ, Kamphorst JJ.
      Pancreatic ductal adenocarcinoma (PDAC) features a near-universal mutation in KRAS. Additionally, the tumor suppressor PTEN is lost in ∼10% of patients, and in mouse models, this dramatically accelerates tumor progression. While oncogenic KRAS and phosphatidylinositol 3-kinase (PI3K) cause divergent metabolic phenotypes individually, how they synergize to promote tumor metabolic alterations and dependencies remains unknown. We show that in KRAS-driven murine PDAC cells, loss of Pten strongly enhances both mTOR signaling and macropinocytosis. Protein scavenging alleviates sensitivity to mTOR inhibition by rescuing AKT phosphorylation at serine 473 and consequently cell proliferation. Combined inhibition of mTOR and lysosomal processing of internalized protein eliminates the macropinocytosis-mediated resistance. Our results indicate that mTORC2, rather than mTORC1, is an important regulator of protein scavenging and that protein-mediated resistance could explain the lack of effectiveness of mTOR inhibitors in certain genetic backgrounds. Concurrent inhibition of mTOR and protein scavenging might be a valuable therapeutic approach.
    Keywords:  AKT; cancer metabolism; mTORC2; macropinocytosis; metabolic scavenging; pancreatic ductal adenocarcinoma
  26. Clin Exp Metastasis. 2020 Feb 22.
    Harihar S, Ray S, Narayanan S, Santhoshkumar A, Ly T, Welch DR.
      KISS1, a metastasis suppressor gene, has been shown to block metastasis without affecting primary tumor formation. Loss of KISS1 leads to invasion and metastasis in multiple cancers, which is the leading cause of cancer morbidity and mortality. The discovery of KISS1 has provided a ray of hope for early clinical diagnosis and for designing effective treatments targeting metastatic cancer. However, this goal requires greater holistic understanding of its mechanism of action. In this review, we go back into history and highlight some key developments, from the discovery of KISS1 to its role in regulating multiple physiological processes including cancer. We discuss key emerging roles for KISS1, specifically interactions with tissue microenvironment to promote dormancy and regulation of tumor cell metabolism, acknowledged as some of the key players in tumor progression and metastasis. We finally discuss strategies whereby KISS1 might be exploited clinically to treat metastasis.
    Keywords:  Dormancy; Hypogonadism; KISS1; Metabolism; Metastasis; Microenvironment; Therapeutic
  27. Oncogene. 2020 Feb 28.
    Du F, Li X, Feng W, Qiao C, Chen J, Jiang M, Qiu Z, Qian M, Tian D, Nie Y, Fan D, Wu K, Xia L.
      Metastasis is a major cause of high recurrence and poor survival of patients with colorectal cancer (CRC), although the mechanisms associated with this process remain poorly understood. In this study, we report a novel mechanism by which SOX13 promotes CRC metastasis by transactivating SNAI2 and c-MET. SOX13 overexpression was significantly correlated with more aggressive clinicopathological features of CRC and indicated poor prognosis in two independent cohorts of CRC patients (cohort I, n = 363; cohort II, n = 390). Overexpression of SOX13-promoted CRC migration, invasion, and metastasis, whereas SOX13 downregulation caused the opposite effects. Further mechanistic investigation identified SNAI2 and MET as important target genes of SOX13 using serial deletion and site-directed mutagenesis luciferase reporter and chromatin immunoprecipitation (ChIP) assays, as well as functional complementation analyses. In addition, SOX13 was shown to be a direct target of HGF/STAT3 signaling, and the c-MET inhibitor crizotinib blocked the HGF/STAT3/SOX13/c-MET axis, significantly inhibiting SOX13-mediated CRC migration, invasion and metastasis. Moreover, in clinical CRC tissues, SOX13 expression was positively correlated with the expression of SNAI2, c-MET, and HGF. CRC patients with positive coexpression of SOX13/SNAI2, SOX13/c-MET, or HGF/SOX13 exhibited a worse prognosis. In summary, SOX13 is a promising prognostic biomarker in patients with CRC, and blocking the HGF/STAT3/SOX13/c-MET axis with crizotinib could be a new therapeutic strategy to prevent SOX13-mediated CRC metastasis.
  28. Theranostics. 2020 ;10(5): 1981-1996
    Sun W, Li J, Zhou L, Han J, Liu R, Zhang H, Ning T, Gao Z, Liu B, Chen X, Ba Y.
      Oxaliplatin (OXA) resistance is the major obstacle to the anticancer effects of chemotherapy in colorectal cancer (CRC) patients. MicroRNAs (miRNAs) play an important role in the chemoresistance of various tumors. Our objective is to clarify the underlying mechanism of miRNAs in chemoresistance and provide a potential strategy to improve the response of CRC patients to chemotherapeutics. Methods: MiRNA microarray and Real-time PCR were performed to compare changes in miRNA expression between oxaliplatin-resistant and the parental cells. CCK8, apoptosis assay, immunofluorescence and xenograft studies were used to elucidate the impact of miR-27b-3p on regulating chemoresistance. Luciferase reporter assay and western blot were carried to assess the regulatory role of miR-27b-3p in ATG10 expression. The effects of miR-27b-3p and ATG10 on autophagy were investigated by GFP-LC3 fluorescence microscopy, transmission electron microscopy, and western blot. ChIP assay and luciferase assay were performed to test the c-Myc's occupancy on the miR-27B promoter. Results: We observed that miR-27b-3p expression was significantly downregulated in oxaliplatin-resistant cell lines (SW480-OxR and HCT116-OxR) compared to the corresponding parental cell lines and that miR-27b-3p expression was positively correlated with disease-free survival (DFS) time in colorectal cancer patients. MiR-27b-3p could sensitize colorectal cancer cells to oxaliplatin in vitro and in vivo. Under oxaliplatin treatment, chemoresistant cells showed a higher autophagy level than parental cells. Moreover, we also identified that miR-27b-3p inhibited the expression of ATG10 at the posttranscriptional level, thus inhibiting autophagy. Further study demonstrated that c-Myc can inhibit the expression of miR-27b-3p via binding to the promoter region of miR-27B gene. Conclusions: Our study identifies a novel c-Myc/miR-27b-3p/ATG10 signaling pathway that regulates colorectal cancer chemoresistance. These results suggest that miR-27b-3p is not only a potential indicator for evaluating efficiency of chemotherapy, but also a valuable therapeutic target for CRC, especially for patients with chemoresistance.
    Keywords:  ATG10; autophagy; chemoresistance; colorectal cancer; miR-27b-3p
  29. FASEB J. 2020 Feb 26.
    Wang C, Liu Q, Huang M, Zhou Q, Zhang X, Zhang J, Xie R, Yu Y, Chen S, Fan J, Chen X.
      Lymph node metastasis is associated with tumor relapse and poor patient prognosis in bladder cancer. However, the mechanisms by which bladder carcinoma cells induce lymphangiogenesis and further promote metastasis in the lymphatic system remain unclear. Here, we show that the transcription factor GATA-binding factor 6 (GATA6) was substantially downregulated in bladder cancer via promoter hypermethylation. Low-level GATA6 expression significantly correlated with lymph node metastasis positivity and was able to predict earlier relapse and shorter survival of bladder cancer. Reconstitution of GATA6 inhibited lymphangiogenesis and lymph node metastasis in GATA6-low bladder cancer cells, while silencing of GATA6 rendered lymphatic metastasis in GATA6-high bladder cancer cells. Additionally, we demonstrated that GATA6 bound to the promoter of vascular endothelial growth factor (VEGF)-C, a lymphangiogenic factor, and acted as a transcriptional repressor. This GATA6/VEGF-C axis was essential for GATA6-mediated lymphatic metastasis. In bladder cancer patients, low GATA6 correlated with high VEGF-C and reduced overall survival. These findings indicate GATA6 as a pivotal regulator in the lymphatic dissemination of bladder cancer and suggest a new therapeutic target for the disease.
    Keywords:  GATA6; VEGF-C; bladder cancer; lymphangiogenesis; metastasis
  30. Biochem Biophys Res Commun. 2020 Feb 22. pii: S0006-291X(20)30365-X. [Epub ahead of print]
    Li Y, Jiang Y, Cheng J, Ma J, Li Q, Pang T.
      Autophagy is related to the development of several tumors including acute myeloid leukemia (AML). Inhibition of autophagy in AML cells can make them more susceptible to chemotherapy. However, the influence of autophagy in mesenchymal stem cells (MSCs) remains inconclusive. In the present study, we demonstrated that the expression of ATG5 and autophagy were elevated in MSCs derived from AML patients (AML-MSCs) compared to healthy donors (HD-MSCs). After inhibiting autophagy by 3-Methyladenine (3 MA) or silencing ATG5, the differentiation potential of AML-MSCs was decreased, the fraction of G0/G1 phase was increased while that of G2 phase was reduced, and the expression of CXCL12 was reduced in AML-MSCs. After co-culture of NB4 and THP1 with MSCs pretreated with 3 MA or ATG5 knockdown respectively, the sensitivity of AML cell lines to daunorubicin and doxorubicin was improved in a dose- and time-dependent manner compared to controls. The increased sensitivity of AML cells to genotoxic agents was related to ERK1/2 and AKT pathway. These results suggested ATG5 mediated potential differentiation capacities and cell cycle distribution of AML-MSCs, and targeting autophagy, especially ATG5 in AML-MSCs could improve the chemosensitivity of AML.
    Keywords:  ATG5; Acute myeloid leukemia; Autophagy; Chemosensitivity; Mesenchymal stem cells