bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒03‒29
thirty-nine papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology


  1. J Exp Med. 2020 Jun 01. pii: e20191787. [Epub ahead of print]217(6):
    Hermanova I, Zúñiga-García P, Caro-Maldonado A, Fernandez-Ruiz S, Salvador F, Martín-Martín N, Zabala-Letona A, Nuñez-Olle M, Torrano V, Camacho L, Lizcano JM, Talamillo A, Carreira S, Gurel B, Cortazar AR, Guiu M, López JI, Martinez-Romero A, Astobiza I, Valcarcel-Jimenez L, Lorente M, Arruabarrena-Aristorena A, Velasco G, Gomez-Muñoz A, Suárez-Cabrera C, Lodewijk I, Flores JM, Sutherland JD, Barrio R, de Bono JS, Paramio JM, Trka J, Graupera M, Gomis RR, Carracedo A.
      Gene dosage is a key defining factor to understand cancer pathogenesis and progression, which requires the development of experimental models that aid better deconstruction of the disease. Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis. Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer. Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis. Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination. Our data suggest that prostate cells can function normally with low activity of LKB1, whereas its complete absence influences prostate cancer pathogenesis and dissemination.
    DOI:  https://doi.org/10.1084/jem.20191787
  2. Semin Cancer Biol. 2020 Mar 19. pii: S1044-579X(20)30075-4. [Epub ahead of print]
    Nicolini A, Rossi G, Ferrari P, Carpi A.
      In the last decade, a large amount of research has focused on elucidating the mechanisms that account for homing disseminated cancer cells (DCCs) from solid tumours to distant organs, which successively progress to overt metastatic disease; this is currently incurable. A better understanding of DCC behaviour is expected to allow detectable metastasis prevention by more effectively targeting 'metastatic seeds before they sprout'. As DCC biology co-evolved with that of the primary tumour, and due to the many similarities between them, the term 'niche' has been borrowed from normal adult stem cells (ASCs) to define the site of DCC metastatic colonisation. Moreover, heterogeneity, survival, protection, stemness and plasticity as well as the prolonged G0-G1 dormant state in the metastatic niche have been the main aspects of intense investigation. Consistent with these findings, in solid cancers with minimal residual disease (MRD), it has been proposed to prolong adjuvant therapy by targeting specific molecular pathway(s) involving DCC dormancy. However, so far, few disappointing clinical data have been reported. As an alternative strategy, because immune-surveillance contributes to the steady state of the DCC population and likely to the G0-G1 state of cancer cells, we have used prolonged immune-modulatory cytostatic chemotherapy, active immune stimulation with an INF-β/IL-2 sequence or drugs inhibiting myeloid-derived suppressor cell (MDSC)/Treg-mediated immune suppression. This strategy, mainly aimed at boosting the immune response, is based on recent findings suggesting the downregulation of immune escape mechanisms as well as other principal hallmarks during the G0-G1 state and/or in MRD. Preliminary clinical and/or laboratory data suggest the efficacy of this strategy in gastrointestinal and some endocrine-dependent cancers. Following this, we propose therapeutic schedules to prevent DCC activation and proliferation in solid cancers at a high risk of relapse or as maintenance therapy in metastatic patients after complete response (CR) to conventional treatment.
    Keywords:  Immunotherapy; cancer; minimal residual disease
    DOI:  https://doi.org/10.1016/j.semcancer.2020.03.009
  3. Nat Genet. 2020 Mar 16.
    Lin KH, Rutter JC, Xie A, Pardieu B, Winn ET, Bello RD, Forget A, Itzykson R, Ahn YR, Dai Z, Sobhan RT, Anderson GR, Singleton KR, Decker AE, Winter PS, Locasale JW, Crawford L, Puissant A, Wood KC.
      Local adaptation directs populations towards environment-specific fitness maxima through acquisition of positively selected traits. However, rapid environmental changes can identify hidden fitness trade-offs that turn adaptation into maladaptation, resulting in evolutionary traps. Cancer, a disease that is prone to drug resistance, is in principle susceptible to such traps. We therefore performed pooled CRISPR-Cas9 knockout screens in acute myeloid leukemia (AML) cells treated with various chemotherapies to map the drug-dependent genetic basis of fitness trade-offs, a concept known as antagonistic pleiotropy (AP). We identified a PRC2-NSD2/3-mediated MYC regulatory axis as a drug-induced AP pathway whose ability to confer resistance to bromodomain inhibition and sensitivity to BCL-2 inhibition templates an evolutionary trap. Across diverse AML cell-line and patient-derived xenograft models, we find that acquisition of resistance to bromodomain inhibition through this pathway exposes coincident hypersensitivity to BCL-2 inhibition. Thus, drug-induced AP can be leveraged to design evolutionary traps that selectively target drug resistance in cancer.
    DOI:  https://doi.org/10.1038/s41588-020-0590-9
  4. Oncogene. 2020 Mar 20.
    Wenzel J, Rose K, Haghighi EB, Lamprecht C, Rauen G, Freihen V, Kesselring R, Boerries M, Hecht A.
      The transcription factor TCF7L2 is indispensable for intestinal tissue homeostasis where it transmits mitogenic Wnt/β-Catenin signals in stem and progenitor cells, from which intestinal tumors arise. Yet, TCF7L2 belongs to the most frequently mutated genes in colorectal cancer (CRC), and tumor-suppressive functions of TCF7L2 were proposed. This apparent paradox warrants to clarify the role of TCF7L2 in colorectal carcinogenesis. Here, we investigated TCF7L2 dependence/independence of CRC cells and the cellular and molecular consequences of TCF7L2 loss-of-function. By genome editing we achieved complete TCF7L2 inactivation in several CRC cell lines without loss of viability, showing that CRC cells have widely lost the strict requirement for TCF7L2. TCF7L2 deficiency impaired G1/S progression, reminiscent of the physiological role of TCF7L2. In addition, TCF7L2-negative cells exhibited morphological changes, enhanced migration, invasion, and collagen adhesion, albeit the severity of the phenotypic alterations manifested in a cell-line-specific fashion. To provide a molecular framework for the observed cellular changes, we performed global transcriptome profiling and identified gene-regulatory networks in which TCF7L2 positively regulates the proto-oncogene MYC, while repressing the cell cycle inhibitors CDKN2C/CDKN2D. Consistent with its function in curbing cell motility and invasion, TCF7L2 directly suppresses the pro-metastatic transcription factor RUNX2 and impinges on the expression of cell adhesion molecules. Altogether, we conclude that the proliferation-stimulating activity of TCF7L2 persists in CRC cells. In addition, TCF7L2 acts as invasion suppressor. Despite its negative impact on cell cycle progression, TCF7L2 loss-of-function may thereby increase malignancy, which could explain why TCF7L2 is mutated in a sizeable fraction of colorectal tumors.
    DOI:  https://doi.org/10.1038/s41388-020-1259-7
  5. Nat Cell Biol. 2020 Mar 16.
    Li F, Yuan P, Rao M, Jin CH, Tang W, Rong YF, Hu YP, Zhang F, Wei T, Yin Q, Liang T, Wu L, Li J, Li D, Liu Y, Lou W, Zhao S, Liu MF.
      Piwi proteins are normally restricted in germ cells to suppress transposons through associations with Piwi-interacting RNAs (piRNAs), but they are also frequently activated in many types of human cancers. A great puzzle is the lack of significant induction of corresponding piRNAs in cancer cells, as we document here in human pancreatic ductal adenocarcinomas (PDACs), which implies that such germline-specific proteins are somehow hijacked to promote tumorigenesis through a different mode of action. Here, we show that in the absence of piRNAs, human PIWIL1 in PDAC functions as an oncoprotein by activating the anaphase promoting complex/cyclosome (APC/C) E3 complex, which then targets a critical cell adhesion-related protein, Pinin, to enhance PDAC metastasis. This is in contrast to piRNA-dependent PIWIL1 ubiquitination and removal by APC/C during late spermiogenesis. These findings unveil a piRNA-dependent mechanism to switch PIWIL1 from a substrate in spermatids to a co-activator of APC/C in human cancer cells.
    DOI:  https://doi.org/10.1038/s41556-020-0486-z
  6. Trends Cancer. 2020 Apr;pii: S2405-8033(20)30059-5. [Epub ahead of print]6(4): 273-276
    Stephens DC, Harris DA.
      For metastasis to occur, cancer cells must exocytose proteases, like matrix metalloproteinases (MMPs), that are key in extracellular matrix (ECM) degradation. Growing evidence suggests that cancer cells use distinct spatial and temporal clustering patterns or organizing 'elements' that facilitate secretory vesicle fusion and the subsequent exocytosis of proteins that contribute to metastasis.
    Keywords:  Rab GTPase; actin cytoskeleton; exocytosis; lipids; matrix metalloproteinases; organizing elements
    DOI:  https://doi.org/10.1016/j.trecan.2020.01.020
  7. Oncogene. 2020 Mar 20.
    Gao Q, Zhou R, Meng Y, Duan R, Wu L, Li R, Deng F, Lin C, Zhao L.
      Long noncoding RNAs (lncRNAs) have been shown to play crucial roles in cancer long noncoding RNAs (lncRNAs) have been known to play crucial roles in cancer development and progression by regulating chromatin dynamics and gene expression. However, only a few lncRNAs with annotated functions in the progression of colorectal cancer (CRC) have been identified to date. In the present study, the expression of lncCMPK2 was upregulated in CRC tissues and positively correlated with clinical stages and lymphatic metastasis. The overexpression of lncCMPK2 promoted the proliferation and cell cycle transition of CRC cells. Conversely, the silencing of lncCMPK2 restricted cell proliferation both in vitro and in vivo. lncCMPK2 was localized to the nucleus of CRC cells, bound to far upstream element binding protein 3 (FUBP3), and guided FUBP3 to the far upstream element (FUSE) of the c-Myc gene to activate transcription. lncCMPK2 also stabilized FUBP3. These results provide novel insights into the functional mechanism of lncCMPK2 in CRC progression and highlight its potential as a biomarker of advanced CRC and therapeutic target.
    DOI:  https://doi.org/10.1038/s41388-020-1266-8
  8. Theranostics. 2020 ;10(8): 3749-3766
    Li D, Ding X, Xie M, Huang Z, Han P, Tian D, Xia L.
      Rationale: Emerging evidence suggests that noncentrosomal microtubules play an essential role in intracellular transport, cell polarity and cell motility. Whether these noncentrosomal microtubules exist or function in cancer cells remains unclear. Methods: The expression and prognostic values of CAMSAP2 and its functional targets were analyzed by immunohistochemistry in two independent HCC cohorts. Immunofluorescence and co-immunoprecipitation were used for detection of CAMSAP2-decorated noncentrosomal microtubule. Chromatin immunoprecipitation and luciferase report assays were used to determine the c-Jun binding sites in HDAC6 promoter region. In vitro migration and invasion assays and in vivo orthotopic metastatic models were utilized to investigate invasion and metastasis. Results: We reported a microtubule minus‑end‑targeting protein, CAMSAP2, is significantly upregulated in hepatocellular carcinoma (HCC) and correlated with poor prognosis. CAMSAP2 was specifically deposited on microtubule minus ends to serve as a "seed" for noncentrosomal microtubule outgrowth in HCC cells. Upon depletion of CAMSAP2, the noncentrosomal microtubule array was transformed into a completely radial centrosomal pattern, thereby impairing HCC cell migration and invasion. We further demonstrated that CAMSAP2 cooperates with EB1 to regulate microtubule dynamics and invasive cell migration via Trio/Rac1 signaling. Strikingly, both immunofluorescence staining and western blotting showed that CAMSAP2 depletion strongly reduced the abundance of acetylated microtubules in HCC cells. Our results revealed that HDAC6, a promising target for cancer therapy, was inversely downregulated in HCC and uniquely endowed with tumor-suppressive activity by regulation CAMSAP2-mediated microtubule acetylation. Mechanistically, CAMSAP2 activates c-Jun to induce transrepression of HDAC6 through Trio-dependent Rac1/JNK pathway. Furthermore, NSC23766, a Rac1-specific inhibitor significantly inhibited CAMSAP2-mediated HCC invasion and metastasis. Conclusions: CAMSAP2 is functionally, mechanistically, and clinically oncogenic in HCC. Targeting CAMSAP2-mediated noncentrosomal microtubule acetylation may provide new therapeutic strategies for HCC metastasis.
    Keywords:  CAMSAP2; HDAC6; acetylation; hepatocellular carcinoma; noncentrosomal microtubule
    DOI:  https://doi.org/10.7150/thno.42596
  9. Theranostics. 2020 ;10(8): 3668-3683
    Liu DL, Lu LL, Dong LL, Liu Y, Bian XY, Lian BF, Xie L, Wen D, Gao DM, Ke AW, Fan J, Wu WZ.
      Dysregulation of microRNA (miRNA) is a frequent event in hepatocellular carcinoma (HCC), but little is known whether it is a bystander or an actual player on residual HCC metastasis during liver microenvironment remodeling initiated by hepatectomy. Methods: The differently expressed miRNAs and mRNAs were identified from RNA-seq data. Western blot, qRT-PCR, fluorescence in situ hybridization, immunofluorescence and immunohistochemical were used to detect the expression of miRNA and mRNA in cell lines and patient tissues. The biological functions were investigated in vitro and in vivo. Chromatin immunoprecipitation, proximity ligation and luciferase reporter assay were used to explore the specific binding of target genes. The expression of HGF/ERBB3 signaling was detected by Western blot. Results: In this study, HGF induced by hepatectomy was shown to promote metastasis of residual HCC cells. miR-17-5p and miR-20a-5p were confirmed to play inhibitory roles on HCC metastasis. And ERBB3 was found to be the common target of miR-17-5p and miR-20a-5p. HCC cells with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 were often more sensitive to response HGF stimuli and to facilitate metastatic colonization both in vitro and in vivo experimental systems. Furthermore, HGF reinforced ERBB3 expression by NF-κB transcriptional activity in a positive feedback loop. Of particular importance, HCC patients with lower levels of miR-17-5p and miR-20a-5p or higher level of ERBB3 had significantly shorter OS and PFS survivals after surgical resection. Conclusion: miR-17-5p and miR-20a-5p could suppress postoperative metastasis of hepatocellular carcinoma via blocking HGF/ERBB3-NF-κB positive feedback loop and offer a new probable strategy for metastasis prevention after HCC resection.
    Keywords:  HGF/ERBB3- NF-κB feedback loop; hepatocellular carcinoma (HCC); miRNA-17-92 cluster; microenvironment remodeling; postoperative metastasis
    DOI:  https://doi.org/10.7150/thno.41365
  10. Oncogene. 2020 Mar 23.
    Li J, Alvero AB, Nuti S, Tedja R, Roberts CM, Pitruzzello M, Li Y, Xiao Q, Zhang S, Gan Y, Wu X, Mor G, Yin G.
      Deaths from ovarian cancer usually occur when patients succumb to overwhelmingly numerous and widespread micrometastasis. Whereas epithelial-mesenchymal transition is required for epithelial ovarian cancer cells to acquire metastatic potential, the cellular phenotype at secondary sites and the mechanisms required for the establishment of metastatic tumors are not fully determined. Using in vitro and in vivo models we show that secondary epithelial ovarian cancer cells (sEOC) do not fully reacquire the molecular signature of the primary epithelial ovarian cancer cells from which they are derived. Despite displaying an epithelial morphology, sEOC maintains a high expression of the mesenchymal effector, TWIST-1. TWIST-1 is however transcriptionally nonfunctional in these cells as it is precluded from binding its E-box by the PcG protein, CBX7. Deletion of CBX7 in sEOC was sufficient to reactivate TWIST-1-induced transcription, prompt mesenchymal transformation, and enhanced tumorigenicity in vivo. This regulation allows secondary tumors to achieve an epithelial morphology while conferring the advantage of prompt reversal to a mesenchymal phenotype upon perturbation of CBX7. We also describe a subclassification of ovarian tumors based on CBX7 and TWIST-1 expression, which predicts clinical outcomes and patient prognosis.
    DOI:  https://doi.org/10.1038/s41388-020-1269-5
  11. Cancer Res. 2020 Mar 25. pii: canres.3095.2019. [Epub ahead of print]
    Mitobe Y, Iino K, Takayama KI, Ikeda K, Suzuki T, Aogi K, Kawabata H, Suzuki Y, Horie-Inoue K, Inoue S.
      Endocrine therapy is standard treatment for estrogen receptor (ER)-positive breast cancer, yet long-term treatment often causes acquired resistance, which results in recurrence and metastasis. Recent studies have revealed that RNA-binding proteins (RBP) are involved in tumorigenesis. Here we demonstrate that PSF/SFPQ is an RBP that potentially predicts poor prognosis of ER-positive breast cancer patients by posttranscriptionally regulating ERα (ESR1) mRNA expression. Strong PSF immunoreactivity correlated with shorter overall survival in ER-positive breast cancer patients. PSF was predominantly expressed in a model of tamoxifen-resistant breast cancer cells, and depletion of PSF attenuated proliferation of cultured cells and xenografted tumors. PSF expression was significantly associated with estrogen signaling. PSF siRNA downregulated ESR1 mRNA by inhibiting nuclear export of the RNA. Integrative analyses of microarray and RNA-immunoprecipitation sequencing also identified SCFD2, TRA2B, and ASPM as targets of PSF. Among the PSF targets, SCFD2 was a poor prognostic indicator of breast cancer and SCFD2 knockdown significantly suppressed breast cancer cell proliferation. Collectively, this study shows that PSF plays a pathophysiological role in ER-positive breast cancer by posttranscriptionaly regulating expression of its target genes such as ESR1 and SCFD2. Overall, PSF and SCFD2 could be potential diagnostic and therapeutic targets for primary and hormone-refractory breast cancers.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3095
  12. Cancer Lett. 2020 Mar 19. pii: S0304-3835(20)30136-1. [Epub ahead of print]
    Kumar A, Deep G.
      Hypoxia is a key feature of solid tumors, associated with disease aggressiveness and poor outcome. Besides undergoing broad intracellular molecular and metabolic adaptations, hypoxic tumor cells extensively communicate with their microenvironment to concoct conditions favorable for their survival, growth and metastatic spread. This mode of communication is through diverse secretory factors including exosomes (extracellular vesicles of endosomal origin and ∼30-150nm in diameter) which could carry package of molecular information including proteins, nucleic acids, lipids, and metabolites wrapped in lipid bilayer. Numerous studies have concluded that hypoxia promotes exosomes secretion by cancer cells. Moreover, exosomal cargo is considerably altered under hypoxia, dictating tumor cells communication with its local and distant microenvironment. In this review, we have summarized the effects of hypoxia on exosomes (ExoHypoxic) secretion and cargo sorting (miRNAs, proteins, lipids and metabolites) as well as their biological effects in local and distant microenvironment. We have described the key molecular mechanisms (e.g. HIF-1α, ceramides, RAB GTPases, tetraspanins, oxidative stress etc) involved in the production of ExoHypoxic. Lastly, we have highlighted the potential usefulness of ExoHypoxic in cancer prognosis as well as therapeutic opportunities in targeting ExoHypoxic.
    Keywords:  Exosomes; HIF-1α; Hypoxia; RAB GTPases; microRNA
    DOI:  https://doi.org/10.1016/j.canlet.2020.03.017
  13. Mol Cancer. 2020 Mar 25. 19(1): 65
    Liang G, Ling Y, Mehrpour M, Saw PE, Liu Z, Tan W, Tian Z, Zhong W, Lin W, Luo Q, Lin Q, Li Q, Zhou Y, Hamai A, Codogno P, Li J, Song E, Gong C.
      BACKGROUND: Although both circular RNAs (circRNAs) and autophagy are associated with the function of breast cancer (BC), whether circRNAs regulate BC progression via autophagy remains unknown. In this study, we aim to explore the regulatory mechanisms and the clinical significance of autophagy-associated circRNAs in BC.METHODS: Autophagy associated circRNAs were screened by circRNAs deep sequencing and validated by qRT-PCR in BC tissues with high- and low- autophagic level. The biological function of autophagy associated circRNAs were assessed by plate colony formation, cell viability, transwells, flow cytometry and orthotopic animal models. For mechanistic study, RNA immunoprecipitation, circRNAs pull-down, Dual luciferase report assay, Western Blot, Immunofluorescence and Immunohistochemical staining were performed.
    RESULTS: An autophagy associated circRNA circCDYL was elevated by 3.2 folds in BC tissues as compared with the adjacent non-cancerous tissues, and circCDYL promoted autophagic level in BC cells via the miR-1275-ATG7/ULK1 axis; Moreover, circCDYL enhanced the malignant progression of BC cells in vitro and in vivo. Clinically, increased circCDYL in the tumor tissues and serum of BC patients was associated with higher tumor burden, shorter survival and poorer clinical response to therapy.
    CONCLUSIONS: circCDYL promotes BC progression via the miR-1275-ATG7/ULK1-autophagic axis and circCDYL could act as a potential prognostic and predictive molecule for breast cancer patients.
    Keywords:  Autophagy; Breast cancer; circCDYL; miRNA sponge
    DOI:  https://doi.org/10.1186/s12943-020-01152-2
  14. Theranostics. 2020 ;10(8): 3833-3848
    Dang Y, Chen J, Feng W, Qiao C, Han W, Nie Y, Wu K, Fan D, Xia L.
      Rationale: Metastasis and recurrence are the primary reasons for the high mortality rate of human hepatocellular carcinoma (HCC) patients. However, the exact mechanism underlying HCC metastasis remains unclear. The Homeobox (HOX) family proteins, which are a highly conserved transcription factor superfamily, play important roles in cancer metastasis. Here, we report a novel role of HOXC10, one of the most upregulated HOX genes in human HCC tissues, in promoting HCC metastasis. Methods: The expression of HOXC10 and its functional targets was detected by immunohistochemistry in two independent human HCC cohorts. Luciferase reporter and chromatin immunoprecipitation assays were used to measure the transcriptional regulation of target genes by HOXC10. The effect of HOXC10-mediated invasion and metastasis were analyzed by Transwell assays and by an orthotopic metastasis model. Results: Elevated expression of HOXC10 was positively correlated with the loss of tumor encapsulation and with higher tumor-nodule-metastasis (TNM) stage and poor prognosis in human HCC. Overexpression of HOXC10 promoted HCC metastasis by upregulating metastasis-related genes, including 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and vasodilator-stimulated phosphoprotein (VASP). Knockdown of PDPK1 and VASP inhibited HOXC10-enhanced HCC metastasis, whereas upregulation of PDPK1 and VASP rescued the decreased metastasis induced by HOXC10 knockdown. Interleukin-1β (IL-1β), which is the ligand of IL-1R1, upregulated HOXC10 expression through the c-Jun NH2-terminal kinase (JNK)/c-Jun pathway. HOXC10 knockdown significantly reduced IL-1β-mediated HCC metastasis. Furthermore, Anakinra, a specific antagonist of IL-1R1, inhibited IL-1β-induced HOXC10 upregulation and HCC metastasis. In human HCC tissues, HOXC10 expression was positively correlated with PDPK1, VASP and IL-1R1 expression, and patients with positive coexpression of HOXC10/PDPK1, HOXC10/VASP or IL-1R1/HOXC10 exhibited the poorest prognosis. Conclusions: Upregulated HOXC10 induced by IL-1β promotes HCC metastasis by transactivating PDPK1 and VASP expression. Thus, our study implicates HOXC10 as a prognostic biomarker, and targeting this pathway may be a promising therapeutic option for the clinical prevention of HCC metastasis.
    Keywords:  hepatocellular carcinoma; homeobox C10; interleukin 1 receptor type 1.; interleukin-1β; metastasis
    DOI:  https://doi.org/10.7150/thno.41712
  15. Trends Cancer. 2020 Apr;pii: S2405-8033(20)30029-7. [Epub ahead of print]6(4): 348-357
    Sinha G, Ferrer AI, Moore CA, Naaldijk Y, Rameshwar P.
      Breast cancer (BC) relapse, despite clinical advancement, remains one of the biggest issues in the field. Intercellular communication, specifically via connexin (Cx)-mediated gap junctions (GJs), play a key role in the long-term survival of these, treatment-resistant breast cancer stem cells (CSCs), allowing for relapse. Both basic and clinical evidence reveal dual roles for GJs, in tumor suppression, generally referred to as dormancy, and progression and metastasis. GJ intercellular communication (GJIC) can be mediated by multiple types of Cxs, depending on the organ to which the BC cells metastasize. This review expands on the differential expression of Cx-mediated GJIC between CSCs and niche cells within a given microenvironment.
    Keywords:  bone marrow; breast cancer; connexin; dormancy; gap junction; metastasis
    DOI:  https://doi.org/10.1016/j.trecan.2020.01.013
  16. Nat Cell Biol. 2020 Mar 23.
    Nishida J, Momoi Y, Miyakuni K, Tamura Y, Takahashi K, Koinuma D, Miyazono K, Ehata S.
      Advanced clear cell renal cell carcinoma (ccRCC) frequently causes systemic inflammation. Recent studies have shown that cancer cells reshape the immune landscape by secreting cytokines or chemokines. This phenotype, called cancer-cell-intrinsic inflammation, triggers a metastatic cascade. Here, we identified the functional role and regulatory mechanism of inflammation driven by advanced ccRCC cells. The inflammatory nature of advanced ccRCC was recapitulated in a preclinical model of ccRCC. Amplification of cancer-cell-intrinsic inflammation during ccRCC progression triggered neutrophil-dependent lung metastasis. Massive expression of inflammation-related genes was transcriptionally activated by epigenetic remodelling through mechanisms such as DNA demethylation and super-enhancer formation. A bromodomain and extra-terminal motif inhibitor synchronously suppressed C-X-C-type chemokines in ccRCC cells and decreased neutrophil-dependent lung metastasis. Overall, our findings provide insight into the nature of inflammatory ccRCC, which triggers metastatic cascades, and suggest a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41556-020-0491-2
  17. Nature. 2020 Mar;579(7800): S10-S11
    Nogrady B.
      
    Keywords:  Cancer; Genomics; Health care
    DOI:  https://doi.org/10.1038/d41586-020-00845-4
  18. Nat Commun. 2020 Mar 24. 11(1): 1533
    Commander R, Wei C, Sharma A, Mouw JK, Burton LJ, Summerbell E, Mahboubi D, Peterson RJ, Konen J, Zhou W, Du Y, Fu H, Shanmugam M, Marcus AI.
      Phenotypic heterogeneity exists within collectively invading packs of tumor cells, suggesting that cellular subtypes cooperate to drive invasion and metastasis. Here, we take a chemical biology approach to probe cell:cell cooperation within the collective invasion pack. These data reveal metabolic heterogeneity within invasive chains, in which leader cells preferentially utilize mitochondrial respiration and trailing follower cells rely on elevated glucose uptake. We define a pyruvate dehydrogenase (PDH) dependency in leader cells that can be therapeutically exploited with the mitochondria-targeting compound alexidine dihydrochloride. In contrast, follower cells highly express glucose transporter 1 (GLUT1), which sustains an elevated level of glucose uptake required to maintain proliferation. Co-targeting of both leader and follower cells with PDH and GLUT1 inhibitors, respectively, inhibits cell growth and collective invasion. Taken together, our work reveals metabolic heterogeneity within the lung cancer collective invasion pack and provides rationale for co-targeting PDH and GLUT1 to inhibit collective invasion.
    DOI:  https://doi.org/10.1038/s41467-020-15219-7
  19. Proc Natl Acad Sci U S A. 2020 Mar 25. pii: 201916498. [Epub ahead of print]
    Park DD, Phoomak C, Xu G, Olney LP, Tran KA, Park SS, Haigh NE, Luxardi G, Lert-Itthiporn W, Shimoda M, Li Q, Matoba N, Fierro F, Wongkham S, Maverakis E, Lebrilla CB.
      Membrane-bound oligosaccharides form the interfacial boundary between the cell and its environment, mediating processes such as adhesion and signaling. These structures can undergo dynamic changes in composition and expression based on cell type, external stimuli, and genetic factors. Glycosylation, therefore, is a promising target of therapeutic interventions for presently incurable forms of advanced cancer. Here, we show that cholangiocarcinoma metastasis is characterized by down-regulation of the Golgi α-mannosidase I coding gene MAN1A1, leading to elevation of extended high-mannose glycans with terminating α-1,2-mannose residues. Subsequent reshaping of the glycome by inhibiting α-mannosidase I resulted in significantly higher migratory and invasive capabilities while masking cell surface mannosylation suppressed metastasis-related phenotypes. Exclusive elucidation of differentially expressed membrane glycoproteins and molecular modeling suggested that extended high-mannose glycosylation at the helical domain of transferrin receptor protein 1 promotes conformational changes that improve noncovalent interaction energies and lead to enhancement of cell migration in metastatic cholangiocarcinoma. The results provide support that α-1,2-mannosylated N-glycans present on cancer cell membrane proteins may serve as therapeutic targets for preventing metastasis.
    Keywords:  cholangiocarcinoma; glycosylation; mass spectrometry; membrane proteins; metastasis
    DOI:  https://doi.org/10.1073/pnas.1916498117
  20. Oncogene. 2020 Mar 19.
    Floren M, Restrepo Cruz S, Termini CM, Marjon KD, Lidke KA, Gillette JM.
      A principal challenge in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. As such, there remains a critical need to identify key regulators of chemotherapy resistance in AML. In this study, we demonstrate that the membrane scaffold, CD82, contributes to the chemoresistant phenotype of AML. Using an RNA-seq approach, we identified the increased expression of the tetraspanin family member, CD82, in response to the chemotherapeutic, daunorubicin. Analysis of the TARGET and BEAT AML databases identifies a correlation between CD82 expression and overall survival of AML patients. Moreover, using a combination of cell lines and patient samples, we find that CD82 overexpression results in significantly reduced cell death in response to chemotherapy. Investigation of the mechanism by which CD82 promotes AML survival in response to chemotherapy identified a crucial role for enhanced protein kinase c alpha (PKCα) signaling and downstream activation of the β1 integrin. In addition, analysis of β1 integrin clustering by super-resolution imaging demonstrates that CD82 expression promotes the formation of dense β1 integrin membrane clusters. Lastly, evaluation of survival signaling following daunorubicin treatment identified robust activation of p38 mitogen-activated protein kinase (MAPK) downstream of PKCα and β1 integrin signaling when CD82 is overexpressed. Together, these data propose a mechanism where CD82 promotes chemoresistance by increasing PKCα activation and downstream activation/clustering of β1 integrin, leading to AML cell survival via activation of p38 MAPK. These observations suggest that the CD82-PKCα signaling axis may be a potential therapeutic target for attenuating chemoresistance signaling in AML.
    DOI:  https://doi.org/10.1038/s41388-020-1261-0
  21. Cancer Lett. 2020 Mar 18. pii: S0304-3835(20)30133-6. [Epub ahead of print]
    Huang F, Ma G, Zhou X, Zhu X, Yu X, Ding F, Cao X, Liu Z.
      Metastasis is still a major cause of cancer-related mortality. Lysosome-associated membrane protein 3 (LAMP3) has been implicated in the invasiveness and metastasis of multiple cancer types; however, the underlying mechanisms are unclear. In this study, we found that LAMP3 was overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and that this increased expression positively correlated with lymph node metastasis. Depletion of LAMP3 dramatically suppressed the motility of ESCC cells in vitro and experimental pulmonary and lymph node metastasis in vivo. Importantly, knockdown of LAMP3 increased the level of phosphorylated VASP(Ser239), which attenuated the invasive and metastatic capability of ESCC cells. We identified that cAMP-dependent protein kinase A (PKA) was responsible for the phosphorylation of VASP at Ser239. Consistently, silencing of PKA regulatory subunits diminished Ser239 phosphorylation on VASP and restored the motility capacity of LAMP3-depleted ESCC cells. In conclusion, we uncovered a previously unknown role of LAMP3 in promoting cellular motility and metastasis in ESCC.
    Keywords:  Esophageal cancer; LAMP3; Metastasis; PKA; VASP
    DOI:  https://doi.org/10.1016/j.canlet.2020.03.014
  22. Nat Genet. 2020 Mar 23.
    Shih DJH, Nayyar N, Bihun I, Dagogo-Jack I, Gill CM, Aquilanti E, Bertalan M, Kaplan A, D'Andrea MR, Chukwueke U, Ippen FM, Alvarez-Breckenridge C, Camarda ND, Lastrapes M, McCabe D, Kuter B, Kaufman B, Strickland MR, Martinez-Gutierrez JC, Nagabhushan D, De Sauvage M, White MD, Castro BA, Hoang K, Kaneb A, Batchelor ED, Paek SH, Park SH, Martinez-Lage M, Berghoff AS, Merrill P, Gerstner ER, Batchelor TT, Frosch MP, Frazier RP, Borger DR, Iafrate AJ, Johnson BE, Santagata S, Preusser M, Cahill DP, Carter SL, Brastianos PK.
      Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.
    DOI:  https://doi.org/10.1038/s41588-020-0592-7
  23. Clin Cancer Res. 2020 Mar 26. pii: clincanres.0097.2020. [Epub ahead of print]
    Piotrowska Z, Hata AN.
      Matched pre-/post-treatment tissue biopsies from EGFR-mutant NSCLC patients demonstrate that histologic transformations, including both SCLC and squamous transformation, are unexpectedly common among patients progressing on first-line osimertinib. The study highlights the key role of tissue testing and underscores the need for innovative therapeutic approaches to prevent, rather than treat, resistance.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-0097
  24. Cancer Immunol Res. 2020 Mar 24. pii: canimm.0483.2019. [Epub ahead of print]
    Ferrari de Andrade L, Kumar S, Luoma A, Ito Y, Alves da Silva PH, Pan D, Pyrdol JW, Yoon CH, Wucherpfennig KW.
      Resistance to cytotoxic T cells is frequently mediated by loss of MHC class I expression or IFNγ signaling in tumor cells, such as mutations of B2M or JAK1 genes. NK cells could potentially target such resistant tumors, but suitable NK cell-based strategies remain to be developed. We hypothesized that such tumors could be targeted by NK cells if sufficient activating signals were provided. Human tumors frequently express the MICA and MICB ligands of the activating NKG2D receptor, but proteolytic shedding of MICA/B represents an important immune evasion mechanism in many human cancers. We showed that B2M- and JAK1-deficient metastases were targeted by NK cells following treatment with a monoclonal antibody (mAb) that blocks MICA/B shedding. We also demonstrated that the FDA-approved HDAC inhibitor panobinostat and a MICA/B antibody acted synergistically to enhance MICA/B surface expression on tumor cells. The HDAC inhibitor enhanced MICA/B gene expression, whereas the MICA/B antibody stabilized the synthesized protein on the cell surface. The combination of panobinostat and the MICA/B antibody reduced the number of pulmonary metastases formed by a human melanoma cell line in NSG mice reconstituted with human NK cells. NK cell-mediated immunity induced by a mAb specific for MICA/B, therefore, provides an opportunity to target tumors with mutations that render them resistant to cytotoxic T cells.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-19-0483
  25. Theranostics. 2020 ;10(8): 3366-3381
    Liao Y, Liu Y, Xia X, Shao Z, Huang C, He J, Jiang L, Tang D, Liu J, Huang H.
      Rationale: Androgen receptor splice variant 7 (AR-V7) is a leading cause of the development of castration-resistant prostate cancer (CRPC). However, the regulation and function of AR-V7 at levels of post-translational modifications in prostate cancer therapy remain poorly understood. Here, we conducted a library screen of natural products to identify potential small molecules responsible for AR-V7 protein degradation in human prostate cancer cell lines. Methods: A natural product library was used to screen the inhibitor of AR-V7. Co-IP and biomass spectrum assays were used to identify the AR-V7-interacting proteins, whereas western blot, confocal microscopy, RNA interfering, and gene transfection were used to validate these interactions. Cell viability, EDU staining, and colony formation assays were employed to detect cell growth and proliferation. Flowcytometry assays were used to detect the distribution of cell cycle. Mouse xenograft models were used to study the anti-CRPC effects in vivo. Results: This screen identified rutaecarpine, one of the major components of the Chinese medicine Evodia rutaecarpa, as a novel chemical that selectively induces AR-V7 protein degradation via K48-linked ubiquitination. Mechanically, this effect relies on rutaecarpine inducing the formation of a GRP78-AR-V7 protein complex, which further recruits the E3 ligase SIAH2 to directly promote the ubiquitination of AR-V7. Consequently, the genetic and pharmacological activation of the GRP78-dependent AR-V7 protein degradation restores the sensitivity of castration-resistant prostate cancer to anti-androgen therapy in cell culture and animal models. Conclusions: These findings not only provide a new approach for overcoming castration-resistance in prostate cancer therapy, but also increase our understanding about the interplay between molecular chaperones and ubiquitin ligase in shaping protein stability.
    Keywords:  AR-V7; CRPC; GRP78; SIAH2; rutaecarpine
    DOI:  https://doi.org/10.7150/thno.41849
  26. Semin Cancer Biol. 2020 Mar 19. pii: S1044-579X(20)30076-6. [Epub ahead of print]
    Ishaq M, Ojha R, Sharma AP, Singh SK.
      Autophagy is being explored as a potential therapeutic target for enhancing the cytotoxic effects of chemotherapeutic regimens in various malignancies. Autophagy plays a very important role in cancer pathogenesis. Here, we discuss the updates on the modulation of autophagy via dynamic interactions with different organelles and the exploitation of selective autophagy for exploring therapeutic strategies. We further discuss the role of autophagy inhibitors in cancer preclinical and clinical trials, novel autophagy inhibitors, and challenges likely to be faced by clinicians while inducting autophagy modulators in clinical practice.
    Keywords:  Autophagy; Cancer; Resistance; Therapy; Tumor immunity
    DOI:  https://doi.org/10.1016/j.semcancer.2020.03.010
  27. Cancer Res. 2020 Mar 26. pii: canres.3147.2019. [Epub ahead of print]
    Selvaggio G, Canato S, Pawar A, Monteiro PT, Guerreiro PS, Brás MM, Janody F, Chaouiya C.
      Epithelial-to-mesenchymal transition (EMT) has been associated with cancer cell heterogeneity, plasticity, and metastasis. However, the extrinsic signals supervising these phenotypic transitions remain elusive. To assess how selected microenvironmental signals control cancer-associated phenotypes along the EMT continuum, we defined a logical model of the EMT cellular network that yields qualitative degrees of cell adhesions by adherens junctions and focal adhesions, two features affected during EMT. The model attractors recovered epithelial, mesenchymal, and hybrid phenotypes. Simulations showed that hybrid phenotypes may arise through independent molecular paths involving stringent extrinsic signals. Of particular interest, model predictions and their experimental validations indicated that: 1) stiffening of the ExtraCellular Matrix (ECM) was a prerequisite for cells overactivating FAK_SRC to upregulate SNAIL and acquire a mesenchymal phenotype, and 2) FAK_SRC inhibition of cell-cell contacts through the Receptor-type tyrosine-protein phosphatases kappa led to acquisition of a full mesenchymal, rather than a hybrid, phenotype. Altogether, these computational and experimental approaches allow assessment of critical microenvironmental signals controlling hybrid EMT phenotypes and indicate that EMT involves multiple molecular programs.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3147
  28. Nat Commun. 2020 Mar 25. 11(1): 1557
    Yasukawa M, Ando Y, Yamashita T, Matsuda Y, Shoji S, Morioka MS, Kawaji H, Shiozawa K, Machitani M, Abe T, Yamada S, Kaneko MK, Kato Y, Furuta Y, Kondo T, Shirouzu M, Hayashizaki Y, Kaneko S, Masutomi K.
      The telomerase reverse transcriptase is upregulated in the majority of human cancers and contributes directly to cell transformation. Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1. Clinicopathological analyses reveal that phosphorylation of hTERT at threonine 249 occurs more frequently in aggressive cancers. Using CRISPR/Cas9 genome editing, we introduce substitution mutations at threonine 249 in the endogenous hTERT locus and find that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase and terminal transferase activities. Cap Analysis of Gene Expression (CAGE) demonstrates that hTERT phosphorylation at 249 regulates the expression of specific genes that are necessary for cancer cell proliferation and tumor formation. These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomere independent manner.
    DOI:  https://doi.org/10.1038/s41467-020-15289-7
  29. Cancer Lett. 2020 Mar 23. pii: S0304-3835(20)30137-3. [Epub ahead of print]
    Qi S, Perrino S, Miao X, Lamarche-Vane N, Brodt P.
      Liver metastases remain a major cause of death from gastrointestinal tract cancers and other malignancies, such as breast and lung carcinomas. Understanding the underlying biology is essential for the design of effective therapies. We previously identified the chemokine CCL7 and its receptor CCR3 as critical mediators of invasion and metastasis in lung and colon carcinoma cells. Here we show that the CCL7/CCR3 axis regulates a late stage in invadopodia genesis namely, the targeting of MMP-9 to the invadopodia complex, thereby promoting invadopodia maturation and collagen degradation. We show that this process could be blocked by overexpression of a dominant negative RhoA in highly invasive cells, while a constitutively active RhoA upregulated invadopodia maturation in CCL7-silenced and poorly invasive and metastatic cells and also enhanced their metastatic potential in vivo, collectively, implicating RhoA activation in signaling downstream of CCL7. Blockade of the ERK or PI3K pathways by chemical inhibitors also inhibited invadopodia formation, but affected the initiation stage of invadopodia genesis. Our data implicate CCL7/CCR3 signaling in invadopodia maturation and suggest that chemokine signaling acts in concert with extracellular matrix-initiated signals to promote invasion and liver metastasis.
    Keywords:  CCL7; Chemokines; MMP-9; colon cancer; extracellular matrix; invadopodia; liver metastasis; lung cancer
    DOI:  https://doi.org/10.1016/j.canlet.2020.03.018
  30. Oncol Lett. 2020 Apr;19(4): 3071-3078
    Liu S, Zhang D, Chen L, Gao S, Huang X.
      Long non-coding RNA BRM (lncBRM) was first identified in liver cancer stem cells and was reported to promote multiple cancer types. However, the function of lncBRM in papillary thyroid carcinoma (PTC) remains unclear. The primary focus of the present study was to determine the biological role of lncBRM in PTC. Reverse transcription-quantitative PCR assays revealed that lncBRM was upregulated in PTC tissues and cells. Cell Counting Kit-8, Transwell invasion and colony-formation assays were performed to assess cell proliferation, invasion and migration, respectively. Furthermore, high expression of lncBRM was associated with poor overall survival time in patients with PTC. lncBRM knockout significantly suppressed cell proliferation, migration and invasion. lncBRM was predicted to bind to microRNA (miR)-331-3p and targets SLC25A1. Overexpression of miR-331-3p or inhibition of SLC25A1 resulted in significantly suppressed proliferation, migration and invasion of PTC cells. Rescue assays demonstrated that inhibition of miR-331-3p significantly abrogated the effects of lncBRM knockout on PTC cell proliferation, migration and invasion. In conclusion, the present study suggests that lncBRM promotes PTC by regulating miR-331-3p and targeting SLC25A1.
    Keywords:  SLC25A1; long non-coding RNA BRM; micoRNA-331-3p; papillary thyroid carcinoma
    DOI:  https://doi.org/10.3892/ol.2020.11418
  31. Trends Cancer. 2020 Apr;pii: S2405-8033(20)30026-1. [Epub ahead of print]6(4): 267-271
    Khatib S, Pomyen Y, Dang H, Wang XW.
      Tumor heterogeneity is a large conundrum in cancer medicine, making most therapeutic interventions palliative rather than curative. Here we discuss the implications of how molecularly targeted therapies in solid malignancies that promote limited cancer cell death may in fact make tumors more heterogeneous, increase aggressive phenotypes, and thus worsen patient outcomes.
    Keywords:  biodiversity; cell death; heterogeneity; tumor evolution
    DOI:  https://doi.org/10.1016/j.trecan.2020.01.010
  32. Nat Rev Urol. 2020 Mar 16.
    Carceles-Cordon M, Kelly WK, Gomella L, Knudsen KE, Rodriguez-Bravo V, Domingo-Domenech J.
      Over the past 5 years, the advent of combination therapeutic strategies has substantially reshaped the clinical management of patients with advanced prostate cancer. However, most of these combination regimens were developed empirically and, despite offering survival benefits, are not enough to halt disease progression. Thus, the development of effective therapeutic strategies that target the mechanisms involved in the acquisition of drug resistance and improve clinical trial design are an unmet clinical need. In this context, we hypothesize that the tumour engineers a dynamic response through the process of cellular rewiring, in which it adapts to the therapy used and develops mechanisms of drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K-AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties. These dynamic responses are specific for each patient and could be responsible for treatment failure despite multi-target approaches. Understanding the common stages of these cellular rewiring mechanisms to gain a new perspective on the molecular underpinnings of drug resistance might help formulate novel combination therapeutic regimens.
    DOI:  https://doi.org/10.1038/s41585-020-0298-8
  33. Mol Cancer Res. 2020 Mar 23. pii: molcanres.1033.2019. [Epub ahead of print]
    Wang M, Zhang G, Zhang Y, Cui X, Wang S, Gao S, Wang Y, Liu Y, Bae JH, Yang WH, Qi LS, Wang L, Liu R.
      Fibrinogen is an extracellular matrix protein composed of three polypeptide chains with fibrinogen alpha (FGA), beta (FGB) and gamma (FGG). While fibrinogen and its related fragments are involved in tumor angiogenesis and metastasis, their functional roles are incompatible. A recent genome-scale screening reveals that loss of FGA affects the acceleration of tumor growth and metastasis of lung cancer, but the mechanism remains elusive. We used CRISPR/Cas9 genome editing to knockout (KO) FGA in human lung adenocarcinoma (LUAD) cell lines A549 and H1299. By colony formation, transwell migration and matrix invasion assays, FGA KO increased cell proliferation, migration, and invasion but decreased the expressions of epithelial-mesenchymal transition marker E-cadherin and cytokeratin 5/8 in A549 and H1299 cells. However, administration of FGA inhibited cell proliferation and migration but induced apoptosis in A549 cells. Of note, FGA KO cells indirectly co-cultured by transwells with FGA wild-type cells increased FGA in the culture medium, leading to decreased migration of FGA KO cells. Furthermore, our functional analysis identified a direct interaction of FGA with integrin α5 as well as FGA-integrin signaling that regulated the AKT-mTOR signaling pathway in A549 cells. In addition, we validated that FGA KO increased tumor growth and metastasis through activation of AKT signaling in an A549 xenograft model. Implications: These findings demonstrate that that loss of FGA facilities tumor growth and metastasis through integrin-AKT signaling pathway in lung cancer.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-19-1033
  34. Theranostics. 2020 ;10(8): 3767-3778
    Xu P, Jiang L, Yang Y, Wu M, Liu B, Shi Y, Shen Q, Jiang X, He Y, Cheng D, Xiong Q, Yang Z, Duan L, Lin J, Zhao S, Shi P, Yang C, Chen Y.
      Purpose: Lung cancer is the leading cause of cancer related deaths worldwide. We have previously identified many differentially expressed genes (DEGs) from large scale pan-cancer dataset using the Cross-Value Association Analysis (CVAA) method. Here we focus on Progestin and AdipoQ Receptor 4 (PAQR4), a member of the progestin and adipoQ receptor (PAQR) family localized in the Golgi apparatus, to determine their clinical role and mechanism in the development of non-small cell lung cancer (NSCLC). Methods: The protein expression profile of PAQR4 was examined by IHC using tissue microarrays, and the effects of PAQR4 on cell proliferation, colony formation and xenograft tumor formation were tested in NSCLC cells. Real-time RT-PCR, co-immunoprecipitation (co-IP) and GST-pulldown assays were used to explore the mechanism of action of PAQR4. Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues. We demonstrated that PAQR4 high expression correlates with a worse clinical outcome, and that its knockdown suppresses cell proliferation by inducing apoptosis. Importantly, overexpressed PAQR4 physically interacts with Nrf2 in NSCLC cells, blocking the interaction between Nrf2 and Keap1. Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.
    Keywords:  Keap1; Nrf2; Progestin and AdipoQ Receptor 4; non-small cell lung cancer; ubiquitination
    DOI:  https://doi.org/10.7150/thno.43142
  35. Sci Transl Med. 2020 Mar 25. pii: eaay8456. [Epub ahead of print]12(536):
    Martin CJ, Datta A, Littlefield C, Kalra A, Chapron C, Wawersik S, Dagbay KB, Brueckner CT, Nikiforov A, Danehy FT, Streich FC, Boston C, Simpson A, Jackson JW, Lin S, Danek N, Faucette RR, Raman P, Capili AD, Buckler A, Carven GJ, Schürpf T.
      Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti-programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor-β (TGFβ) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFβ isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFβ isoform expressed in many types of human tumors, suggesting that TGFβ1 may be a key contributor to primary CBT resistance. To test whether selective TGFβ1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFβ1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti-PD-1 antibody in mice harboring syngeneic tumors refractory to anti-PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFβ1 was also effective in tumors expressing more than one TGFβ isoform. Combined SRK-181-mIgG1 and anti-PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFβ1 activation may avoid dose-limiting toxicities previously observed with pan-TGFβ inhibitors. These results establish a rationale for exploring selective TGFβ1 inhibition to overcome primary resistance to CBT.
    DOI:  https://doi.org/10.1126/scitranslmed.aay8456
  36. Mol Cancer Res. 2020 Mar 26. pii: molcanres.1020.2019. [Epub ahead of print]
    Zhang ZJ, Xiao Q, Li XY.
      Thyroid cancer (TC) is the most common endocrine malignancy, and miR-574 is significantly up-regulated in TC. However, the role and underlying mechanism of miR-574 in TC development are poorly understood. In this study, we showed that NF-κB/p65 signaling pathway was activated and miR-574 was up-regulated in TC cells. p65 directly bound to the promoter of miR-574 and activated miR-574 transcription. Functionally, miR-574 inhibited apoptosis, promoted proliferation and migration of TC cells, and stimulated TC-induced tube formation of endothelial cells. On the molecular level, miR-574 inhibited the expression of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) by binding to 3'-UTR of BNIP3. miR-574 also down-regulated the expression of apoptosis-inducing factor (AIF), while elevated the levels of MMP2, MMP9, and VEGFA. In vivo, miR-574 promoted xenograft growth, which was associated with reduced apoptosis and enhanced angiogenesis. NF-B/miR-574 signaling presents multiple oncogenic activities on TC development by directly regulating the BNIP3/AIF pathway. Therefore, targeting NF-B/miR-574 signaling may reduce the aggressiveness of TC. Implications: miR-574, directly regulated by NF-κB/p65, promotes tumorigenesis of thyroid cancer via inhibiting BNIP3/AIF pathway.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-19-1020