bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒11‒29
twenty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. Oncogene. 2020 Nov 25.
    Yang Y, Ma Y, Gao H, Peng T, Shi H, Tang Y, Li H, Chen L, Hu K, Han A.
      Ewing sarcoma (ES) is a type of highly aggressive pediatric tumor in bones and soft tissues and its metastatic spread remains the most powerful predictor of poor outcome. We previously identified that the transcription factor hepatoma-derived growth factor (HDGF) promotes ES tumorigenesis. However, the mechanisms underlying ES metastasis remain unclear. Here, we show that HDGF drives ES metastasis in vitro and in vivo, and HDGF reduces metastasis-free survival (MFS) in two independent large cohorts of human ES patients. Integrative analyses of HDGF ChIP-seq and gene expression profiling in ES cells reveal that HDGF regulates multiple metastasis-associated genes, among which activated leukocyte cell adhesion molecule (ALCAM) emerges as a major HDGF target and a novel metastasis-suppressor in ES. HDGF down-regulates ALCAM, induces expression and activation of the downstream effectors Rho-GTPase Rac1 and Cdc42, and promotes actin cytoskeleton remodeling and cell-matrix adhesion. In addition, repression of ALCAM and activation of Rac1 and Cdc42 are required for the pro-metastatic functions of HDGF in vitro. Moreover, analyses in murine models with ES tumor orthotopic implantation and experimental metastasis, as well as in human ES samples, demonstrate the associations among HDGF, ALCAM, and GTPases expression levels. Furthermore, high HDGF/low ALCAM expression define a subgroup of patients harboring the worst MFS. These findings suggest that the HDGF/ALCAM/GTPases axis represents a promising therapeutic target for limiting ES metastasis.
    DOI:  https://doi.org/10.1038/s41388-020-01485-8
  2. Cancer Res. 2020 Nov 25. pii: canres.1865.2020. [Epub ahead of print]
    Chuang CH, Dorsch M, Dujardin P, Silas S, Ueffing K, Hölken JM, Yang D, Winslow MM, Grüner BM.
      Lung cancer is a prevalent and lethal cancer type that leads to more deaths than the next four major cancer types combined. Metastatic cancer spread is responsible for most cancer deaths but the cellular changes that enable cancer cells to leave the primary tumor and establish inoperable and lethal metastases remain poorly understood. To uncover genes that are specifically required to sustain metastasis survival or growth, we performed a genome-scale pooled lentiviral-shRNA library screen in cells that represent non-metastatic and metastatic states of lung adenocarcinoma. Mitochondrial ribosome and mitochondria-associated genes were identified as top gene sets associated with metastasis-specific lethality. Metastasis-derived cell lines in vitro and metastases analyzed ex vivo from an autochthonous lung cancer mouse model had lower mitochondrial membrane potential and reduced mitochondrial functionality than non-metastatic primary tumors. Electron microscopy of metastases uncovered irregular mitochondria with bridging and loss of normal membrane structure. Consistent with these findings, compounds that inhibit mitochondrial translation or replication had a greater effect on the growth of metastasis-derived cells. Finally, mice with established tumors developed fewer metastases upon treatment with phenformin in vivo. These results suggest that the metastatic cell state in lung adenocarcinoma is associated with a specifically altered mitochondrial functionality that can be therapeutically exploited.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1865
  3. Dev Cell. 2020 Nov 03. pii: S1534-5807(20)30801-7. [Epub ahead of print]
    Gensbittel V, Kräter M, Harlepp S, Busnelli I, Guck J, Goetz JG.
      The most dangerous aspect of cancer lies in metastatic progression. Tumor cells will successfully form life-threatening metastases when they undergo sequential steps along a journey from the primary tumor to distant organs. From a biomechanics standpoint, growth, invasion, intravasation, circulation, arrest/adhesion, and extravasation of tumor cells demand particular cell-mechanical properties in order to survive and complete the metastatic cascade. With metastatic cells usually being softer than their non-malignant counterparts, high deformability for both the cell and its nucleus is thought to offer a significant advantage for metastatic potential. However, it is still unclear whether there is a finely tuned but fixed mechanical state that accommodates all mechanical features required for survival throughout the cascade or whether tumor cells need to dynamically refine their properties and intracellular components at each new step encountered. Here, we review the various mechanical requirements successful cancer cells might need to fulfill along their journey and speculate on the possibility that they dynamically adapt their properties accordingly. The mechanical signature of a successful cancer cell might actually be its ability to adapt to the successive microenvironmental constraints along the different steps of the journey.
    Keywords:  deformability; mechanical phenotype; mechanical stress; mechanosensing; metastasis; stiffness; tumor cell mechanics
    DOI:  https://doi.org/10.1016/j.devcel.2020.10.011
  4. Front Oncol. 2020 ;10 554272
    Wolfe K, Kamata R, Coutinho K, Inoue T, Sasaki AT.
      Despite advances in targeted therapeutics and understanding in molecular mechanisms, metastasis remains a substantial obstacle for cancer treatment. Acquired genetic mutations and transcriptional changes can promote the spread of primary tumor cells to distant tissues. Additionally, recent studies have uncovered that metabolic reprogramming of cancer cells is tightly associated with cancer metastasis. However, whether intracellular metabolism is spatially and temporally regulated for cancer cell migration and invasion is understudied. In this review, we highlight the emergence of a concept, termed "membraneless metabolic compartmentalization," as one of the critical mechanisms that determines the metastatic capacity of cancer cells. In particular, we focus on the compartmentalization of purine nucleotide metabolism (e.g., ATP and GTP) at the leading edge of migrating cancer cells through the uniquely phase-separated microdomains where dynamic exchange of nucleotide metabolic enzymes takes place. We will discuss how future insights may usher in a novel class of therapeutics specifically targeting the metabolic compartmentalization that drives tumor metastasis.
    Keywords:  GTP-metabolism; cancer; leading edge; liquid-liquid phase separation; membraneless metabolic compartmentalization; metabolon; metastasis; purine biosynthesis
    DOI:  https://doi.org/10.3389/fonc.2020.554272
  5. Proc Natl Acad Sci U S A. 2020 Nov 23. pii: 202017152. [Epub ahead of print]
    Yi J, Zhu J, Wu J, Thompson CB, Jiang X.
      Ferroptosis, a form of regulated necrosis driven by iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various signaling pathways related to cancer. In this study, we found that activating mutation of phosphatidylinositol 3-kinase (PI3K) or loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function, highly frequent events in human cancer, confers ferroptosis resistance in cancer cells, and that inhibition of the PI3K-AKT-mTOR signaling axis sensitizes cancer cells to ferroptosis induction. Mechanistically, this resistance requires sustained activation of mTORC1 and the mechanistic target of rapamycin (mTOR)C1-dependent induction of sterol regulatory element-binding protein 1 (SREBP1), a central transcription factor regulating lipid metabolism. Furthermore, stearoyl-CoA desaturase-1 (SCD1), a transcriptional target of SREBP1, mediates the ferroptosis-suppressing activity of SREBP1 by producing monounsaturated fatty acids. Genetic or pharmacologic ablation of SREBP1 or SCD1 sensitized ferroptosis in cancer cells with PI3K-AKT-mTOR pathway mutation. Conversely, ectopic expression of SREPB1 or SCD1 restored ferroptosis resistance in these cells, even when mTORC1 was inhibited. In xenograft mouse models for PI3K-mutated breast cancer and PTEN-defective prostate cancer, the combination of mTORC1 inhibition with ferroptosis induction resulted in near-complete tumor regression. In conclusion, hyperactive mutation of PI3K-AKT-mTOR signaling protects cancer cells from oxidative stress and ferroptotic death through SREBP1/SCD1-mediated lipogenesis, and combination of mTORC1 inhibition with ferroptosis induction shows therapeutic promise in preclinical models.
    Keywords:  SREBP1; cancer; ferroptosis; lipogenesis; mTOR
    DOI:  https://doi.org/10.1073/pnas.2017152117
  6. Mol Cancer. 2020 11 23. 19(1): 163
    Xu J, Wan Z, Tang M, Lin Z, Jiang S, Ji L, Gorshkov K, Mao Q, Xia S, Cen D, Zheng J, Liang X, Cai X.
      BACKGROUND AND AIMS: Accumulating evidence suggests that the primary and acquired resistance of hepatocellular carcinoma (HCC) to sorafenib is mediated by multiple molecular, cellular, and microenvironmental mechanisms. Understanding these mechanisms will enhance the likelihood of effective sorafenib therapy.METHODS: In vitro and in vivo experiments were performed and clinical samples and online databases were acquired for clinical investigation.
    RESULTS: In this study, we found that a circular RNA, circRNA-SORE, which is up-regulated in sorafenib-resistant HCC cells, was necessary for the maintenance of sorafenib resistance, and that silencing circRNA-SORE substantially increased the efficacy of sorafenib-induced apoptosis. Mechanistic studies determined that circRNA-SORE sequestered miR-103a-2-5p and miR-660-3p by acting as a microRNA sponge, thereby competitively activating the Wnt/β-catenin pathway and inducing sorafenib resistance. The increased level of circRNA-SORE in sorafenib-resistant cells resulted from increased RNA stability. This was caused by an increased level of N6-methyladenosine (m6A) at a specific adenosine in circRNA-SORE. In vivo delivery of circRNA-SORE interfering RNA by local short hairpin RNA lentivirus injection substantially enhanced sorafenib efficacy in animal models.
    CONCLUSIONS: This work indicates a novel mechanism for maintaining sorafenib resistance and is a proof-of-concept study for targeting circRNA-SORE in sorafenib-treated HCC patients as a novel pharmaceutical intervention for advanced HCC.
    Keywords:  Circular RNA; Hepatocellular carcinoma; Sorafenib resistance; m6A
    DOI:  https://doi.org/10.1186/s12943-020-01281-8
  7. Mol Ther. 2020 Nov 19. pii: S1525-0016(20)30620-1. [Epub ahead of print]
    Tian X, Yu H, Li D, Jin G, Dai S, Gong P, Kong C, Wang X.
      Epigenetic deregulation, especially mutagenesis or the abnormal expression of epigenetic regulatory factors (ERFs) plays an important role in malignant tumorigenesis. To screen natural inhibitors of breast cancer metastasis, we adopted small interfering RNAs to transiently knock down 591 ERF-coding genes in luminal breast cancer MCF-7 cells and found that depletion of AF9 significantly promoted MCF-7 cell invasion and migration. A mouse model of metastasis further confirmed the suppressive role of AF9 in breast cancer metastasis. RNA profiling revealed enrichment of AF9 targets genes in the epithelial-mesenchymal transition (EMT). Mechanistically, tandem mass spectrometry showed that AF9 interacts with Snail, which hampers Snail transcriptional activity in basal-like breast cancer (BLBC) cells. AF9 reconstitutes an activated state on the promoter of Snail, which is a master regulator of EMT, and derepresses genes by recruiting CBP or GCN5. Additionally, miR-5694 targeted and degraded AF9 messenger RNA (mRNA) in BLBC cells, further enhancing cell invasion and migration. Notably, AF9 and miR-5694 expression in BLBC clinical samples correlated inversely. Hence, miR-5694 mediates downregulation of AF9 and provides metastatic advantages in BLBC. Restoring expression of the metastasis suppressor AF9 is a possible therapeutic strategy against metastatic breast cancer.
    Keywords:  AF9; BLBC; Breast cancer metastasis; Epigenetic regulatory factors; Snail; miR-5694
    DOI:  https://doi.org/10.1016/j.ymthe.2020.11.022
  8. Mol Cancer. 2020 11 23. 19(1): 164
    Chen LY, Wang L, Ren YX, Pang Z, Liu Y, Sun XD, Tu J, Zhi Z, Qin Y, Sun LN, Li JM.
      BACKGROUND: Circular RNA (circRNAs) and hypoxia have been found to play the key roles in the pathogenesis and progression of cancer including colorectal cancer (CRC). However, the expressions and functions of the specific circRNAs in regulating hypoxia-involved CRC metastasis, and the circRNAs that are relevant to regulate HIF-1α levels in CRC remain elusive.METHODS: qRT-PCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to analyze the location of circ-ERBIN. Function-based experiments were performed using circ-ERBIN overexpression and knockdown cell lines in vitro and in vivo, including CCK8, colony formation, EdU assay, transwell, tumor growth and metastasis models. Mechanistically, luciferase reporter assay, western blots and immunohistochemical stainings were performed.
    RESULTS: Circ-Erbin was highly expressed in the CRC cells and Circ-Erbin overexpression facilitated the proliferation, migration and metastasis of CRC in vitro and in vivo. Notably, circ-Erbin overexpression significantly promoted angiogenesis by increasing the expression of hypoxia induced factor (HIF-1α) in CRC. Mechanistically, circ-Erbin accelerated a cap-independent protein translation of HIF-1α in CRC cells as the sponges of miR-125a-5p and miR-138-5p, which synergistically targeted eukaryotic translation initiation factor 4E binding protein 1(4EBP-1).
    CONCLUSIONS: Our findings uncover a key mechanism for circ-Erbin mediated HIF-1α activation by miR-125a-5p-5p/miR-138-5p/4EBP-1 axis and circ-ERBIN is a potential target for CRC treatment.
    Keywords:  Circular RNA; Colorectal cancer; hypoxia; miRNA sponge
    DOI:  https://doi.org/10.1186/s12943-020-01272-9
  9. Trends Cancer. 2020 Nov 23. pii: S2405-8033(20)30287-9. [Epub ahead of print]
    Gottlieb B, Trifiro M, Batist G.
      Tumor genetic heterogeneity, in which individual tumors contain both multiple variant cancer-associated and normal genes, has been widely reported, although its significance has yet to be fully understood. We propose a genetic heterogeneity-based selection-centric hypothesis in which genetic heterogeneity, caused by the temporary reduction of DNA repair efficiency, occurs very early in human development, resulting in a small minority of cells in normal tissues acquiring cancer-associated genes that remain dormant. Cancer develops when precancer cells are selected for by altered tissue microenvironments; similar scenarios occur with development of metastases and therapeutic resistance in established cancer. This suggests that a normal cell selection treatment approach based on preferentially selecting normal cells within tumors may be effective in treating cancer.
    Keywords:  genetic heterogeneity-based selection-centric cancer hypothesis; normal cell selection treatment approach; tumor genetic heterogeneity
    DOI:  https://doi.org/10.1016/j.trecan.2020.10.013
  10. Cell Rep. 2020 Nov 24. pii: S2211-1247(20)31410-8. [Epub ahead of print]33(8): 108421
    Shen S, Faouzi S, Souquere S, Roy S, Routier E, Libenciuc C, André F, Pierron G, Scoazec JY, Robert C.
      Emerging evidence indicates that non-mutational drug tolerance mechanisms underlie the survival of residual cancer "persister" cells. Here, we find that BRAF(V600E) mutant melanoma persister cells tolerant to BRAF/MEK inhibitors switch their metabolism from glycolysis to oxidative respiration supported by peroxisomal fatty acid β-oxidation (FAO) that is transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPARα). Knockdown of the key peroxisomal FAO enzyme, acyl-CoA oxidase 1 (ACOX1), as well as treatment with the peroxisomal FAO inhibitor thioridazine, specifically suppresses the oxidative respiration of persister cells and significantly decreases their emergence. Consistently, a combination treatment of BRAF/MEK inhibitors with thioridazine in human-melanoma-bearing mice results in a durable anti-tumor response. In BRAF(V600E) melanoma samples from patients treated with BRAF/MEK inhibitors, higher baseline expression of FAO-related genes and PPARα correlates with patients' outcomes. These results pave the way for a metabolic strategy to overcome drug resistance.
    Keywords:  fatty acid oxidation; melanoma; peroxisome; persistent cancer cell; targeted therapy
    DOI:  https://doi.org/10.1016/j.celrep.2020.108421
  11. Cancer Res. 2020 Nov 23. pii: canres.0622.2020. [Epub ahead of print]
    Mestre-Farrera A, Bruch-Oms M, Peña R, Rodríguez-Morató J, Alba-Castellón L, Comerma L, Quintela-Fandino M, Duñach M, Baulida J, Pozo ÓJ, García de Herreros A.
      Tumors are complex tissues composed of transformed epithelial cells as well as cancer-activated fibroblasts (CAF) that facilitate epithelial tumor cell invasion. We show here that CAF and other mesenchymal cells rely much more on glutamine than epithelial tumor cells; consequently, they are more sensitive to inhibition of glutaminase. Glutamine dependence drove CAF migration towards this amino acid when cultured in low glutamine conditions. CAF also invaded a Matrigel matrix following a glutamine concentration gradient and enhanced the invasion of tumor cells when both cells were co-cultured. Accordingly, glutamine directed invasion of xenografted tumors in immunocompromised mice. Stimulation of glutamine-driven epithelial tumor invasion by fibroblasts required previous CAF activation which involved the TGFb/Snail1 signaling axis. CAF migration towards Gln presented a polarized Akt2 distribution that was modulated by the Gln-dependent activity of TRAF6 and p62 in the migrating front, and depletion of these proteins prevented Akt2 polarization and Gln-driven CAF invasion. Our results demonstrate that glutamine deprivation promotes CAF migration and invasion, which in turn facilitates the movement of tumor epithelial cells towards nutrient-rich territories. These results provide a novel molecular mechanism for how metabolic stress enhances invasion and metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0622
  12. Cancers (Basel). 2020 Nov 20. pii: E3461. [Epub ahead of print]12(11):
    Silva VR, Neves SP, Santos LS, Dias RB, Bezerra DP.
      Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells-while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed.
    Keywords:  autophagy; cancer; cell death; drug resistance
    DOI:  https://doi.org/10.3390/cancers12113461
  13. Mol Cancer. 2020 Nov 28. 19(1): 167
    Chen S, Shen X.
      Evidence indicates that long non-coding RNAs (lncRNAs) play a crucial role in the carcinogenesis and progression of a wide variety of human malignancies including colon cancer. In this review, we describe the functions and mechanisms of lncRNAs involved in colon oncogenesis, such as HOTAIR, PVT1, H19, MALAT1, SNHG1, SNHG7, SNHG15, TUG1, XIST, ROR and ZEB1-AS1. We summarize the roles of lncRNAs in regulating cell proliferation, cell apoptotic death, the cell cycle, cell migrative and invasive ability, epithelial-mesenchymal transition (EMT), cancer stem cells and drug resistance in colon cancer. In addition, we briefly highlight the functions of circRNAs in colon tumorigenesis and progression, including circPPP1R12A, circPIP5K1A, circCTIC1, circ_0001313, circRNA_104916 and circRNA-ACAP2. This review provides the rationale for anticancer therapy via modulation of lncRNAs and circular RNAs (circRNAs) in colon carcinoma.
    Keywords:  Colon cancer; LncRNAs; Proliferation; Therapy; miRNAs
    DOI:  https://doi.org/10.1186/s12943-020-01287-2
  14. Cancers (Basel). 2020 Nov 19. pii: E3444. [Epub ahead of print]12(11):
    Cheriyamundath S, Ben-Ze'ev A.
      Cell adhesion to neighboring cells is a fundamental biological process in multicellular organisms that is required for tissue morphogenesis. A tight coordination between cell-cell adhesion, signaling, and gene expression is a characteristic feature of normal tissues. Changes, and often disruption of this coordination, are common during invasive and metastatic cancer development. The Wnt/β-catenin signaling pathway is an excellent model for studying the role of adhesion-mediated signaling in colorectal cancer (CRC) invasion and metastasis, because β-catenin has a dual role in the cell; it is a major adhesion linker of cadherin transmembrane receptors to the cytoskeleton and, in addition, it is also a key transducer of Wnt signaling to the nucleus, where it acts as a co-transcriptional activator of Wnt target genes. Hyperactivation of Wnt/β-catenin signaling is a common feature in the majority of CRC patients. We found that the neural cell adhesion receptor L1CAM (L1) is a target gene of β-catenin signaling and is induced in carcinoma cells of CRC patients, where it plays an important role in CRC metastasis. In this review, we will discuss studies on β-catenin target genes activated during CRC development (in particular, L1), the signaling pathways affected by L1, and the role of downstream target genes activated by L1 overexpression, especially those that are also part of the intestinal stem cell gene signature. As intestinal stem cells are highly regulated by Wnt signaling and are believed to also play major roles in CRC progression, unravelling the mechanisms underlying the regulation of these genes will shed light on both normal intestinal homeostasis and the development of invasive and metastatic CRC.
    Keywords:  EMT; L1; Lgr5; NF-κB; Wnt target genes; cancer stem cells; cell adhesion; colon cancer; invasion and metastasis; β-catenin
    DOI:  https://doi.org/10.3390/cancers12113444
  15. Nat Commun. 2020 Nov 26. 11(1): 5998
    Spinler K, Bajaj J, Ito T, Zimdahl B, Hamilton M, Ahmadi A, Koechlein CS, Lytle N, Kwon HY, Anower-E-Khuda F, Sun H, Blevins A, Weeks J, Kritzik M, Karlseder J, Ginsberg MH, Park PW, Esko JD, Reya T.
      Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin β7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgβ7 signaling axis as a key regulatory control point for bcCML growth and dissemination.
    DOI:  https://doi.org/10.1038/s41467-020-19782-x
  16. Cancer Discov. 2020 Nov 25.
      A new artificial intelligence-based predictive modeling framework called DrugCell could accurately predict effective drugs and treatment combinations based on tumor genotype, according to a proof-of-concept analysis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NB2020-109
  17. Cancer Res. 2020 Nov 25. pii: canres.2066.2020. [Epub ahead of print]
    Davra V, Kumar S, Geng K, Calianese D, Mehta D, Gadiyar V, Kasikara C, Lahey KC, Chang YJ, Wichroski M, Gao C, De Lorenzo MS, Kotenko SV, Bergsbaken T, Mishra PK, Gause WC, Quigley M, Spires TE, Birge RB.
      Despite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, current strategies have limited success in breast cancer, indicating that additional inhibitory pathways are required to complement existing therapeutics. TAM receptors (Tyro-3, Axl, and Mertk) are often correlated with poor prognosis due to their capacities to sustain an immunosuppressive environment. Here we ablate Axl on tumor cells using CRISPR/Cas9 gene editing, and by targeting Mertk in the tumor microenvironment, we observe distinct functions of TAM as oncogenic kinases as well as inhibitory immune receptors. Depletion of Axl suppressed cell intrinsic oncogenic properties, decreased tumor growth, reduced the incidence of lung metastasis and increased overall survival of mice when injected into mammary fatpad of syngeneic mice, and demonstrated synergy when combined with anti-PD1 therapy. Blockade of Mertk function on macrophages decreased efferocytosis, altered the cytokine milieu, and resulted in suppressed macrophage gene expression patterns. Mertk KO mice or treatment with anti-Mertk neutralizing mAb also altered the cellular immune profile, resulting in a more inflamed tumor environment with enhanced T cell infiltration into tumors and T cell-mediated cytotoxicity. The anti-tumor activity from Mertk inhibition was abrogated by depletion of cytotoxic CD8α T cells by using anti-CD8α mAb or by transplantation of tumor cells into B6.CB17-Prkdc SCID mice. Our data indicate that targeting Axl expressed on tumor cells and Mertk in the tumor microenvironment are predicted to have a combinatorial benefit to enhance current immunotherapies and that Axl and Mertk have distinct functional activities that impair host anti-tumor response.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2066
  18. Cancer Res. 2020 Nov 25. pii: canres.1876.2020. [Epub ahead of print]
    Shen M, Xie S, Rowicki M, Michel S, Wei Y, Hang X, Wan L, Lu X, Yuan M, Jin JF, Jaschinski F, Zhou T, Klar R, Kang Y.
      Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that Metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASOs) that effectively and specifically suppress MTDH expression in vitro and in vivo. Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1876
  19. Mol Cancer. 2020 11 24. 19(1): 166
    Gao W, Guo H, Niu M, Zheng X, Zhang Y, Xue X, Bo Y, Guan X, Li Z, Guo Y, He L, Zhang Y, Li L, Cao J, Wu Y.
      BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the second most common malignant tumor in head and neck. Autophagy and circular RNAs (circRNAs) play critical roles in cancer progression and chemoresistance. However, the function and mechanism of circRNA in autophagy regulation of LSCC remain unclear.METHODS: The autophagy-suppressive circRNA circPARD3 was identified via RNA sequencing of 107 LSCC tissues and paired adjacent normal mucosal (ANM) tissues and high-content screening. RT-PCR, Sanger sequencing, qPCR and fluorescence in situ hybridization were performed to detect circPARD3 expression and subcellular localization. Biological functions of circPARD3 were assessed by proliferation, migration, invasion, autophagic flux, and chemoresistance assays using in vitro and in vivo models. The mechanism of circPARD3 was investigated by RNA immunoprecipitation, RNA pulldown, luciferase reporter assays, western blotting and immunohistochemical staining.
    RESULTS: Autophagy was inhibited in LSCC, and circPARD3 was upregulated in the LSCC tissues (n = 100, p < 0.001). High circPARD3 level was associated with advanced T stages (p < 0.05), N stages (p = 0.001), clinical stages (p < 0.001), poor differentiation degree (p = 0.025), and poor prognosis (p = 0.002) of LSCC patients (n = 100). Functionally, circPARD3 inhibited autophagy and promoted LSCC cell proliferation, migration, invasion and chemoresistance. We further revealed that activation of the PRKCI-Akt-mTOR pathway through sponging miR-145-5p was the main mechanism of circPARD3 inhibited autophagy, promoting LSCC progression and chemoresistance.
    CONCLUSION: Our study reveals that the novel autophagy-suppressive circPARD3 promotes LSCC progression and chemoresistance through the PRKCI-Akt-mTOR pathway, providing new insights into circRNA-mediated autophagy regulation and potential biomarker and target for LSCC treatment.
    Keywords:  Autophagy; Chemoresistance; Circular RNA; Migration and invasion; PI3K-Akt-mTOR signaling pathway; PRKCI
    DOI:  https://doi.org/10.1186/s12943-020-01279-2
  20. Nat Commun. 2020 Nov 27. 11(1): 6064
    Kermani AA, Macdonald CB, Burata OE, Ben Koff B, Koide A, Denbaum E, Koide S, Stockbridge RB.
      By providing broad resistance to environmental biocides, transporters from the small multidrug resistance (SMR) family drive the spread of multidrug resistance cassettes among bacterial populations. A fundamental understanding of substrate selectivity by SMR transporters is needed to identify the types of selective pressures that contribute to this process. Using solid-supported membrane electrophysiology, we find that promiscuous transport of hydrophobic substituted cations is a general feature of SMR transporters. To understand the molecular basis for promiscuity, we solved X-ray crystal structures of a SMR transporter Gdx-Clo in complex with substrates to a maximum resolution of 2.3 Å. These structures confirm the family's extremely rare dual topology architecture and reveal a cleft between two helices that provides accommodation in the membrane for the hydrophobic substituents of transported drug-like cations.
    DOI:  https://doi.org/10.1038/s41467-020-19820-8
  21. Proc Natl Acad Sci U S A. 2020 Nov 23. pii: 201920338. [Epub ahead of print]
    An S, Cho SY, Kang J, Lee S, Kim HS, Min DJ, Son E, Cho KH.
      Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.
    Keywords:  PDK1; cellular senescence; network modeling; skin aging; systems biology
    DOI:  https://doi.org/10.1073/pnas.1920338117