bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒09‒05
twenty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Commun. 2021 Sep 02. 12(1): 5232
      Disseminated tumor cells often fall into a long term of dormant stage, characterized by decreased proliferation but sustained survival, in distant organs before awakening for metastatic growth. However, the regulatory mechanism of metastatic dormancy and awakening is largely unknown. Here, we show that the epithelial-like and mesenchymal-like subpopulations of breast cancer stem-like cells (BCSCs) demonstrate different levels of dormancy and tumorigenicity in lungs. The long non-coding RNA (lncRNA) NR2F1-AS1 (NAS1) is up-regulated in the dormant mesenchymal-like BCSCs, and functionally promotes tumor dissemination but reduces proliferation in lungs. Mechanistically, NAS1 binds to NR2F1 mRNA and recruits the RNA-binding protein PTBP1 to promote internal ribosome entry site (IRES)-mediated NR2F1 translation, thus leading to suppression of ΔNp63 transcription by NR2F1. Furthermore, ΔNp63 downregulation results in epithelial-mesenchymal transition, reduced tumorigenicity and enhanced dormancy of cancer cells in lungs. Overall, the study links BCSC plasticity with metastatic dormancy, and reveals the lncRNA as an important regulator of both processes.
  2. Cancer Res. 2021 Aug 30. pii: canres.1496.2020. [Epub ahead of print]
      Metastatic melanoma is challenging to clinically address. Although standard of care targeted therapy has high response rates in patients with BRAF-mutant melanoma, therapy relapse occurs in most cases. Intrinsically resistant melanoma cells drive therapy resistance and display molecular and biologic properties akin to neural crest-like stem cells (NCLSCs) including high invasiveness, plasticity and self-renewal capacity. The shared transcriptional programs and vulnerabilities between NCLSCs and cancer cells remains poorly understood. Here, we identify a developmental LPAR1-axis critical for NCLSC viability and melanoma cell survival. LPAR1 activity increased during progression and following acquisition of therapeutic resistance. Notably, genetic inhibition of LPAR1 potentiated BRAFi +/- MEKi efficacy and ablated melanoma migration and invasion. Our data defines LPAR1 as a new therapeutic target in melanoma and highlights the promise of dissecting stem cell-like pathways hijacked by tumor cells.
  3. Cancer Res. 2021 Sep 02. pii: canres.0356.2021. [Epub ahead of print]
      Uterine leiomyosarcoma (ULMS) is a malignancy that arises from the uterine smooth muscle. Due to its rarity, aggressive nature, and extremely poor prognosis, the molecular mechanisms driving ULMS remain elusive. To identify candidate cancer genes (CCG) driving ULMS, we conducted an in vivo Sleeping Beauty (SB) transposon mutagenesis screen in uterine myometrium-specific, Pten knockout, Kras mutant (PtenKO/Kras) mice. ULMS quickly developed in SB PtenKO/Kras mice, but not in Pten KO/Kras mice, demonstrating the critical importance of SB mutagenesis for driving ULMS in this model. Subsequent sequencing of SB insertion sites in these tumors identified 19 ULMS CCGs that were significantly enriched in known cancer genes. Among them, Zfp217 and Sfmbt2 functioned at early stages of tumor initiation and appeared to be oncogenes. Expression of ZNF217, the human homolog of Zfp217, was shown to be elevated in human ULMS compared to paired normal uterine smooth muscle, where it negatively correlated with patient prognosis. Inhibition of ZNF217 suppressed, while overexpression induced, proliferation, survival, migration, and stemness of human ULMS. In a second ex-vivo ULMS SB metastasis screen, three CCGs were identified that may drive ULMS metastasis to the lung. One of these CCGs, Nrd1 (NRDC in humans), showed stronger expression in human metastatic tumors compared to primary ULMS and negatively associated with patient survival. NRDC knockdown impaired migration and adhesion without affecting cell proliferation, while overexpression had the opposite effect. Together, these results reveal novel mechanism driving ULMS tumorigenesis and metastasis and identify ZNF217 and NRDC as potential targets for ULMS therapy.
  4. Nat Commun. 2021 08 31. 12(1): 5196
      Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER+ tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER+ breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER+ breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER+ breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER+ tumor, suggesting its preventive use for bone recurrence in ER+ patients.
  5. Cancer Discov. 2021 Sep 03.
      Researchers have developed a machine learning method that could help advance research on tumorigenesis. Using large databases of human tumors, the team developed machine learning models that can identify driver and passenger mutations in specific cancer genes and determine the location and key features of cancer drivers.
  6. Oncogene. 2021 Sep 01.
      Yes-associated protein 1 (YAP1), a key player in the Hippo pathway, has been shown to play a critical role in tumor progression. However, the role of YAP1 in prostate cancer cell invasion, migration, and metastasis is not well defined. Through functional, transcriptomic, epigenomic, and proteomic analyses, we showed that prolyl hydroxylation of YAP1 plays a critical role in the suppression of cell migration, invasion, and metastasis in prostate cancer. Knockdown (KD) or knockout (KO) of YAP1 led to an increase in cell migration, invasion, and metastasis in prostate cancer cells. Microarray analysis showed that the EMT pathway was activated in Yap1-KD cells. ChIP-seq analysis showed that YAP1 target genes are enriched in pathways regulating cell migration. Mass spectrometry analysis identified P4H prolyl hydroxylase in the YAP1 complex and YAP1 was hydroxylated at multiple proline residues. Proline-to-alanine mutations of YAP1 isoform 3 identified proline 174 as a critical residue, and its hydroxylation suppressed cell migration, invasion, and metastasis. KO of P4ha2 led to an increase in cell migration and invasion, which was reversed upon Yap1 KD. Our study identified a novel regulatory mechanism of YAP1 by which P4HA2-dependent prolyl hydroxylation of YAP1 determines its transcriptional activities and its function in prostate cancer metastasis.
  7. Cancer Cell. 2021 Sep 01. pii: S1535-6108(21)00445-1. [Epub ahead of print]
      Tumor-associated macrophages (TAMs) promote metastasis and inhibit T cells, but macrophages can be polarized to kill cancer cells. Macrophage polarization could thus be a strategy for controlling cancer. We show that macrophages from metastatic pleural effusions of breast cancer patients can be polarized to kill cancer cells with monophosphoryl lipid A (MPLA) and interferon (IFN) γ. MPLA + IFNγ injected intratumorally or intraperitoneally reduces primary tumor growth and metastasis in breast cancer mouse models, suppresses metastasis, and enhances chemotherapy response in an ovarian cancer model. Both macrophages and T cells are critical for the treatment's anti-metastatic effects. MPLA + IFNγ stimulates type I IFN signaling, reprograms CD206+ TAMs to inducible NO synthase (iNOS)+ macrophages, and activates cytotoxic T cells through macrophage-secreted interleukin-2 (IL-12) and tumor necrosis factor alpha (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for engaging a systemic anti-tumor immune response.
    Keywords:  IFNγ; MPLA; anti-tumor immune response; breast cancer; cytotoxic T cells; metastasis treatment; ovarian cancer; tumor-associated macrophages
  8. Cancer Discov. 2021 Sep 03. pii: candisc.0003.2021. [Epub ahead of print]
      Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an interferon-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand Rae1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide and immune checkpoint blockade to patients with immune desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low-T cell infiltrated tumors.
  9. Cancer Res. 2021 Sep 01. pii: canres.1254.2021. [Epub ahead of print]
      To study progression of bladder cancer from non-muscle invasive to muscle invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo, thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle invasive bladder tumors. Furthermore, pre-invasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including pro-inflammatory pathways. Cross species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle invasive disease.
  10. EMBO Rep. 2021 Sep 01. e53391
      The success of cancer immunotherapy is limited to a subset of patients, highlighting the need to identify the processes by which tumors evade immunity. Using CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of LUBAC, are highly susceptible to both NK and CD8+ T-cell-mediated killing. We demonstrate that HOIP-deficient tumor cells exhibit increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8+ T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augment tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory axis, involving HOIP, which limits a transcription-dependent form of cell death that engages both intrinsic and extrinsic apoptotic machinery upon exposure to TNF and IFN-γ. Our findings highlight HOIP inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy.
    Keywords:  CRISPR screen; HOIP; IFN-gamma; TNF; immunotherapy
  11. J Clin Invest. 2021 Aug 31. pii: 145035. [Epub ahead of print]
      Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited due to intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically-approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic anti-tumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.
    Keywords:  Cancer; Drug screens; Molecular biology; Oncology
  12. Trends Cell Biol. 2021 Aug 31. pii: S0962-8924(21)00162-8. [Epub ahead of print]
      Modification of the extracellular matrix (ECM) is a critical aspect of developing a metastasis-supportive organ niche. Recent work investigating ECM changes that facilitate metastasis has revealed ways in which different metastatic organ niches are similar as well as the distinct characteristics that make them unique. In this review, we present recent findings regarding how ECM modifications support metastasis in four frequent metastatic sites: the lung, liver, bone, and brain. We discuss ways in which these modifications are shared between metastatic organs as well as features specific to each location. We also discuss areas of technical innovation that could be advantageous to future research and areas of inquiry that merit further investigation.
    Keywords:  extracellular matrix; fibrosis; matrisome; metastasis; microenvironment; premetastatic niche
  13. Cancer Discov. 2021 Sep;11(9): 2126-2128
      Most, but not all, patients with microsatellite-unstable gastric cancer respond to anti-PD-1 therapy. In this issue, Kwon and colleagues show, first, that differences in tumor mutation burden (TMB) may drive this variation in outcomes and, second, that treatment with immune checkpoint inhibitors leads to further immunoediting and a reduction in TMB in responding patients.See related article by Kwon et al., p. 2168.
  14. Clin Cancer Res. 2021 Sep 02. pii: clincanres.1104.2021. [Epub ahead of print]
      PURPOSE: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histological tumor type.PATIENTS AND METHODS: Patients with treatment-refractory BRCA1/2 mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In DRUP, patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB, defined as objective response or stable disease {greater than or equal to} 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model.
    RESULTS: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with bi-allelic BRCA LoF had CB. In 17 patients with - and seven without current labeled indication, 10 and four patients had CB respectively. Treatment resistance in four patients with bi-allelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification and CDKN2A loss, in three tumor types.
    CONCLUSION: These data indicate that PARPi is a promising treatment strategy for patients with non-BRCA associated histologies harboring bi-allelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and HRD signature as well as oncogenic drivers that may contribute to resistance, using a single assay.
  15. Mol Cancer. 2021 Aug 31. 20(1): 112
      BACKGROUND: Circular RNAs (circRNAs) are widely expressed in human cells and are closely associated with cancer development. However, they have rarely been investigated in the context of nasopharyngeal carcinoma (NPC).METHODS: We screened a new circRNA, circRNF13, in NPC cells using next-generation sequencing of mRNA. Reverse transcription polymerase chain reaction and RNA fluorescence in situ hybridization were used to detect circRNF13 expression in 12 non-tumor nasopharyngeal epithelial (NPE) tissues and 36 NPC samples. Cell proliferation was detected using MTT and flow cytometry assays, and colony formation capability was detected using colony formation assays. Cell migration and invasion were analyzed using wound-healing and Transwell assays, respectively. Cell glycolysis was analyzed using the Seahorse glycolytic stress test. Glucose transporter type 1 (GLUT1) ubiquitination and SUMOylation modifications were analyzed using co-immunoprecipitation and western blotting. CircRNF13 and Small Ubiquitin-like Modifier 2 (SUMO2) interactions were analyzed using RNA pull-down and luciferase reporter assays. Finally, to test whether circRNF13 inhibited NPC proliferation and metastasis in vivo, we used a xenograft nude mouse model generated by means of subcutaneous or tail vein injection.
    RESULTS: We found that circRNF13 was stably expressed at low levels in NPC clinical tissues and NPC cells. In vitro and in vivo experiments showed that circRNF13 inhibited NPC proliferation and metastasis. Moreover, circRNF13 activated the SUMO2 protein by binding to the 3'- Untranslated Region (3'-UTR) of the SUMO2 gene and prolonging the half-life of SUMO2 mRNA. Upregulation of SUMO2 promotes GLUT1 degradation through SUMOylation and ubiquitination of GLUT1, which regulates the AMPK-mTOR pathway by inhibiting glycolysis, ultimately resulting in the proliferation and metastasis of NPC.
    CONCLUSIONS: Our results revealed that a novel circRNF13 plays an important role in the development of NPC through the circRNF13-SUMO2-GLUT1 axis. This study implies that circRNF13 mediates glycolysis in NPC by binding to SUMO2 and provides an important theoretical basis for further elucidating the pathogenesis of NPC and targeted therapy.
    Keywords:  GLUT1; Glycolysis; Metastasis; Nasopharyngeal carcinoma; Proliferation; SUMO2; circRNF13
  16. Cancer Res. 2021 Sep 01. pii: canres.1466.2021. [Epub ahead of print]
      Tremendous advances have been made in cancer immunotherapy over the last decade. Among the different steps of gene expression, translation of mRNA is emerging as an essential player in both cancer and immunity. Changes in mRNA translation are both rapid and adaptive, and translational reprogramming is known to be necessary for sustaining cancer cell proliferation. However, the role of mRNA translation in shaping an immune microenvironment permissive to tumors has not been extensively studied. Recent studies on immunotherapy approaches have indicated critical roles of mRNA translation in regulating the expression of immune checkpoint proteins, tuning the secretion of inflammation-associated factors, modulating the differentiation of immune cells in the tumor microenvironment, and promoting cancer resistance to immunotherapies. Careful consideration of the role of mRNA translation in the tumor-immune ecosystem could suggest more effective therapeutic strategies and may eventually change the current paradigm of cancer immunotherapy. In this review, we discuss recent advances in understanding the relationship between mRNA translation and tumor-associated immunity, the potential mechanisms of immunotherapy resistance in cancers linked to translational reprogramming, and therapeutic perspectives and potential challenges of modulating translational regulation in cancer immunotherapy.
  17. Clin Cancer Res. 2021 Aug 31. pii: clincanres.2103.2021. [Epub ahead of print]
      PURPOSE: The companion diagnostic test for trastuzumab has not changed much in the last 25 years. We used high-plex digital spatial profiling to identify biomarkers besides HER2 that can help predict response to trastuzumab in HER2-positive breast cancer.EXPERIMENTAL DESIGN: Fifty-eight protein targets were measured in three different molecularly defined compartments by the NanoString® GeoMx® Digital Spatial Profiler (DSP) in a tissue microarray containing 151 breast cancer patients that received adjuvant trastuzumab as part of the HeCOG 10/05 clinical trial. Promising candidate biomarkers were orthogonally validated with quantitative immunofluorescence (QIF). RNA sequencing data from the NeoALTTO study were accessed to provide independent cohort validation. Disease-free survival (DFS) was the main outcome assessed. Statistical analyses were performed using a two-sided test (α=0.05) and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1).
    RESULTS: By DSP, high expression of alpha-smooth muscle actin (α-SMA), both in the leukocyte and stromal compartments, was associated with shorter DFS in univariate analysis (P = .002 and P = .023, respectively). High α-SMA expression in the stroma was validated by QIF after controlling for ER and PR status (HR, 3.12; 95% CI, 1.12-8.68; P = .029) showing recurrence on trastuzumab in the same cohort. In the NeoALTTO cohort, elevated levels of ACTA2 were predictive for shorter DFS in the multivariate analysis (HR, 3.21; 95% CI, 1.14-9.05; P = .027).
    CONCLUSIONS: This work identifies α-SMA as a novel, easy-to-implement biomarker of resistance to trastuzumab that may be valuable in settings where trastuzumab is combined with other therapies.
  18. Mol Ther. 2021 Jun 08. pii: S1525-0016(21)00312-9. [Epub ahead of print]
      Cisplatin resistance is a major therapeutic challenge in advanced head and neck squamous cell carcinoma (HNSCC). Here, we aimed to investigate the key signaling pathway for cisplatin resistance in HNSCC cells. Vomeronasal type-1 receptor 5 (VN1R5) was identified as a cisplatin resistance-related protein and was highly expressed in cisplatin-resistant HNSCC cells and tissues. The long noncoding RNA (lncRNA) lnc-POP1-1 was confirmed to be a downstream target induced by VN1R5. VN1R5 transcriptionally regulated lnc-POP1-1 expression by activating the specificity protein 1 (Sp1) transcription factor via the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. VN1R5 promoted cisplatin resistance in HNSCC cells in a lnc-POP1-1-dependent manner. Mechanistically, lnc-POP1-1 bound to the minichromosome maintenance deficient 5 (MCM5) protein directly and decelerated MCM5 degradation by inhibiting ubiquitination of the MCM5 protein, which facilitated the repair of DNA damage caused by cisplatin. In summary, we identified the cisplatin resistance-related protein VN1R5 and its downstream target lnc-POP1-1. Upon upregulation by VN1R5, lnc-POP1-1 promotes DNA repair in HNSCC cells through interaction with MCM5 and deceleration of its degradation.
    Keywords:  DNA repair; cisplatin resistance; head and neck squamous cell carcinoma; lnc-POP1-1; long noncoding RNA; minichromosome maintenance deficient 5; specificity protein 1; ubiquitination; vomeronasal type-1 receptor 5
  19. EMBO J. 2021 Aug 30. e108647
      The process of epithelial-mesenchymal transition (EMT) is fundamental for embryonic morphogenesis. Cells undergoing it lose epithelial characteristics and integrity, acquire mesenchymal features, and become motile. In cancer, this program is hijacked to confer essential changes in morphology and motility that fuel invasion. In addition, EMT is increasingly understood to orchestrate a large variety of complementary cancer features, such as tumor cell stemness, tumorigenicity, resistance to therapy and adaptation to changes in the microenvironment. In this review, we summarize recent findings related to these various classical and non-classical functions, and introduce EMT as a true tumorigenic multi-tool, involved in many aspects of cancer. We suggest that therapeutic targeting of the EMT process will-if acknowledging these complexities-be a possibility to concurrently interfere with tumor progression on many levels.
    Keywords:  EMT; MET; SLUG; SNAIL; TWIST; ZEB1; ZEB2; cancer; cell plasticity; hybrid EMT; invasion; metastasis; partial EMT; signaling pathways; tumor stemness