bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒04‒10
fourteen papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Trends Cancer. 2022 Mar 31. pii: S2405-8033(22)00065-6. [Epub ahead of print]
      Genetic studies suggest that sequential dissemination from a primary metastasis, usually at the bone, is a major route of metastatic progression in early, radically resected cancer. Disseminated tumor cells (DTCs) can likely infiltrate but not grow, and may remain dormant once disseminated for extended intervals (from months to decades). The stationary nature of DTCs prevents them from being successfully treated as an asymptomatic residual disease in the adjuvant setting; critically, they can eventually relapse, adapt, and develop therapy resistance, causing incurable overt metastasis. Metastatic lesions usually first appear in one tissue, which invigorates metastatic cells for further dissemination to other organs, with a fatal outcome. Clinical and genetic data now indicate that metastatic lesions in one organ can seed secondary metastases in other organs: in other words, metastasis arising from metastasis. Herein we discuss recent insight into metastasis cell dormancy mechanisms, survival, communication with the local microenvironment, and eventual changes that endow DTCs with the capacity to expand and colonize to other metastatic sites.
    Keywords:  adaptation; dormancy; evolution; metastasis; microenvironment
  2. Cancer Discov. 2022 Apr 01. 12(4): 885
      Adaptation to oxidative stress in a soft microenvironment confers metastatic therapeutic resistance.
  3. Cancer Res. 2022 Apr 08. pii: canres.4349.2021. [Epub ahead of print]
      Circular RNAs (circRNAs) containing retained introns are normally sequestered in the nucleus. Dysregulation of cellular homeostasis can drive their nuclear export, which may be involved in cancer metastasis. However, the mechanism underlying circRNAs nuclear export and its role in lymph node (LN) metastasis of bladder cancer (BCa) remain unclear. Here, we identify an intron-retained circRNA, circNCOR1, that is significantly downregulated in LN metastatic BCa and is negatively associated with poor prognosis of patients. Overexpression of circNCOR1 inhibited lymphangiogenesis and LN metastasis of BCa in vitro and in vivo. Nuclear circNCOR1 epigenetically promoted SMAD7 transcription by increasing heterogeneous nuclear ribonucleoprotein L (hnRNPL)-induced H3K9 acetylation in the SMAD7 promoter, leading to inhibition of the TGFβ-SMAD signaling pathway. Nuclear retention of circNCOR1 was regulated by SUMOylation of DDX39B, an essential regulatory factor responsible for circRNA nuclear-cytoplasmic transport. Reduced SUMO2 binding to DDX39B markedly increased circNCOR1 retention in the nucleus to suppress BCa LN metastasis. By contrast, SUMOylated DDX39B activated nuclear export of circNCOR1, impairing the suppressive role of circNCOR1 on TGFβ-SMAD cascade activation and BCa LN metastasis. In patient-derived xenograft (PDX) models, overexpression of circNCOR1 and inhibition of TGFβ signaling significantly repressed tumor growth and LN metastasis. This study highlights SUMOylation-induced nuclear export of circNCOR1 as a key event regulating TGFβ-SMAD signaling and BCa lymphangiogenesis, thus supporting circNCOR1 as a novel therapeutic agent for patients with LN metastatic BCa.
  4. Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00343-6. [Epub ahead of print]39(1): 110595
      Bioinformatic analysis of 94 patient-derived xenografts (PDXs), cell lines, and organoids (PCOs) identifies three intrinsic transcriptional subtypes of metastatic castration-resistant prostate cancer: androgen receptor (AR) pathway + prostate cancer (PC) (ARPC), mesenchymal and stem-like PC (MSPC), and neuroendocrine PC (NEPC). A sizable proportion of castration-resistant and metastatic stage PC (M-CRPC) cases are admixtures of ARPC and MSPC. Analysis of clinical datasets and mechanistic studies indicates that MSPC arises from ARPC as a consequence of therapy-induced lineage plasticity. AR blockade with enzalutamide induces (1) transcriptional silencing of TP53 and hence dedifferentiation to a hybrid epithelial and mesenchymal and stem-like state and (2) inhibition of BMP signaling, which promotes resistance to AR inhibition. Enzalutamide-tolerant LNCaP cells re-enter the cell cycle in response to neuregulin and generate metastasis in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibits efficacy in models of ARPC and MSPC or MSPC, respectively. These results define MSPC, trace its origin to therapy-induced lineage plasticity, and reveal its sensitivity to HER2/3 inhibition.
    Keywords:  BMP-SMAD signaling; CP: Cancer; TP53; androgen receptor signaling; prostate cancer
  5. Mol Cancer. 2022 Apr 02. 21(1): 92
      BACKGROUND: Circular RNAs (circRNAs) are involved in regulatory processes of ubiquitination and deubiquitination in various tumors at post-transcriptional epigenetic modification level. However, the underlying mechanism and its biological functions of circRNAs in the advanced laryngeal squamous cell carcinoma (LSCC) remain obscure.METHODS: RNA sequencing and quantitative real-time PCR (qRT-PCR) assays were applied to screen for circRNAs differentially expressed in LSCC tissues and cell lines. The candidate RNA-binding proteins and target signalling pathway were detected by RNA pull-down and mass spectrometry, in situ hybridization (ISH), immunohistochemistry (IHC), qRT-PCR assays, and bioinformatics analysis. The functional roles of these molecules were investigated using in vitro and in vivo experiments including EdU, transwell, wound healing, western blot assays, and the xenograft mice models. The molecular mechanisms were identified using RNA pull-down assays, RNA immunoprecipitation (RIP), Co-IP, ISH, Ubiquitination assay, bioinformatics analysis, and the rescue experiments.
    RESULTS: Here, we unveil that microtubule cross-linking factor 1 circRNA (circMTCL1, circ0000825) exerts its critical oncogenic functions by promoting complement C1q-binding protein (C1QBP)-dependent ubiquitin degradation and subsequently activating Wnt/β-catenin signalling in laryngeal carcinoma initiation and development. Specifically, circMTCL1 was remarkably up-regulated in the paired tissues of patients with LSCC (n = 67), which predicted a worse clinical outcome. Functionally, circMTCL1 exerted oncogenic biological charactersistics by promoting cell proliferative capability and invasive and migrative abilities. Ectopic circMTCL1 augumented cell proliferation, migration, and invasion of LSCC cells, and this effect could be reversed by C1QBP knocking down in vitro and in vivo. Mechanistically, circMTCL1 directly recruited C1QBP protein by harboring the specific recognized sequence (+ 159 - + 210), thereby accelerating the translation of C1QBP expression by inhibiting its ubiquitin-proteasome-mediated degradation. Importantly, the direct interaction of C1QBP with β-catenin protein was enhanced via suppressing the β-catenin phosphorylation and accelerating its accumulation in cytoplasm and nucleus.
    CONCLUSION: Our findings manifested a novel circMTCL1-C1QBP-β-catenin signaling axis involving in LSCC tumorigenesis and progression, which shed new light on circRNAs-ubiquitous acidic glycoprotein mediated ubiquitin degradation and provided strategies and targets in the therapeutic intervention of LSCC.
    Keywords:  C1QBP; Laryngeal neoplasms; Ubiquitylation; circRNA MTCL1; β-Catenin
  6. Nat Commun. 2022 Apr 07. 13(1): 1899
      Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a "two cell type" whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.
  7. Cancer Res. 2022 Apr 01. 82(7): 1353-1364
      Tumor relapse after chemotherapy relies on the reconstruction of damaged tumor vasculature. In this context, proangiogenic Tie2-expressing macrophages have been suggested to serve as crucial instructors of tumor revascularization by secreting angiogenic factors while being closely associated with the vessel wall. Although the proangiogenic nature of Tie2+ macrophages is well described, the functional contribution of macrophage Tie2 expression remains elusive. Here, we employed a Cre-loxP system to specifically delete Tie2 in macrophages. In multiple syngeneic solid tumor models and two distinct chemotherapeutic treatment regimens, macrophage-expressed Tie2 did not contribute to primary tumor growth, tumor revascularization after chemotherapy, tumor recurrence, or metastasis. Exposing cultured murine macrophage cell lines and bone marrow-derived macrophages to hypoxia or stimulating them with Ang2 did not induce expression of Tie2 at the RNA or protein level. Furthermore, a comprehensive meta-analysis of publicly available single cell RNA sequencing datasets of human and murine tumor-infiltrating CD11b+ myeloid cells did not reveal a transcriptionally distinct macrophage population marked by the expression of Tie2. Collectively, these data question the previously reported critical role of Tie2-expressing macrophages for tumor angiogenesis and tumor relapse after chemotherapy. Moreover, lack of Tie2 inducibility and absence of Tie2-positive macrophages in multiple recently published tumor studies refute a possible prognostic value of macrophage-expressed Tie2.SIGNIFICANCE: Multiple preclinical tumor models, cell stimulation experiments, and meta-analysis of published tumor single cell RNA sequencing data challenge the reported role of Tie2-positive macrophages for tumor angiogenesis, metastasis, and relapse after chemotherapy. See related commentary by Zhang and Brekken, p. 1172.
  8. Mol Cancer. 2022 Apr 04. 21(1): 95
      Breast cancer continues to be a major global problem with significant mortality associated with advanced stage and metastases at clinical presentation. However, several findings suggest that metastasis is indeed an early occurrence. The standard diagnostic techniques such as invasive core needle biopsy, serological protein marker assays, and non-invasive radiological imaging do not provide information about the presence and molecular profile of small fractions of early metastatic tumor cells which are prematurely dispersed in the circulatory system. These circulating tumor cells (CTCs) diverge from the primary tumors as clusters with a defined secretome comprised of circulating cell-free nucleic acids and small microRNAs (miRNAs). These circulatory biomarkers provide a blueprint of the mutational profile of the tumor burden and tumor associated alterations in the molecular signaling pathways involved in oncogenesis. Amidst the multitude of circulatory biomarkers, miRNAs serve as relatively stable and precise biomarkers in the blood for the early detection of CTCs, and promote step-wise disease progression by executing paracrine signaling that transforms the microenvironment to guide the metastatic CTCs to anchor at a conducive new organ. Random sampling of easily accessible patient blood or its serum/plasma derivatives and other bodily fluids collectively known as liquid biopsy (LB), forms an efficient alternative to tissue biopsies. In this review, we discuss in detail the divergence of early metastases as CTCs and the involvement of miRNAs as detectable blood-based diagnostic biomarkers that warrant a timely screening of cancer, serial monitoring of therapeutic response, and the dynamic molecular adaptations induced by miRNAs on CTCs in guiding primary and second-line systemic therapy.
    Keywords:  Biomarkers; Breast cancer; Cell-free nucleic acids; Circulating tumor cells; Liquid biopsy; Metastasis; microRNAs
  9. Cancer Discov. 2022 Apr 01. 12(4): OF9
      Tumor-derived GABA promotes cancer cell proliferation and immunosuppression through β-catenin.
  10. Oncogene. 2022 Apr 04.
      Dietary cholesterol has been implicated to promote lung cancer. Lung adenocarcinoma (LAC) is a main type of lung cancer, whereas the functional mechanism of cholesterol in LAC remained largely unknown. In the present study, we evidenced that cholesterol promoted cell proliferation and invasion of LAC in vitro as well as LAC metastasis in vivo. Cyp27A1 knockdown reduced the cholesterol-induced LAC cells proliferation and invasion. In contrast, Cyp7B1 knockdown enhanced the effect of cholesterol on LAC cells proliferation and invasion. Furthermore, Cyp27A1 deficiency remarkably reduced high cholesterol-induced LAC metastasis in vivo. Mechanism investigation demonstrated that exposure of LAC cells to 27-hydroxycholesterol induced the phosphorylation of AKT and NFκB p65, and promoted the expression of peptidylprolyl isomerase B (PPIB), especially in the coculture with THP1-derived macrophage. Meanwhile, 27-hydroxycholesterol induced the secretion of FGF2 and IL-6, which contributed to the expression of snail and vimentin. Luciferase report assay and ChIP assay confirmed that NFκB p65 controlled the transcription of PPIB. Inhibiting NFκB p65 activation reduced PPIB expression. PPIB inhibition reduced 27-hydroxycholesterol-induced expression of snail and vimentin. These results indicated that 27-hydroxycholesterol linked high cholesterol and LAC metastasis by regulating NFκB/PPIB axis and the secretion of FGF2 and IL-6.
  11. Cell. 2022 Apr 05. pii: S0092-8674(22)00260-4. [Epub ahead of print]
      Tumor-resident intracellular microbiota is an emerging tumor component that has been documented for a variety of cancer types with unclear biological functions. Here, we explored the functional significance of these intratumor bacteria, primarily using a murine spontaneous breast-tumor model MMTV-PyMT. We found that depletion of intratumor bacteria significantly reduced lung metastasis without affecting primary tumor growth. During metastatic colonization, intratumor bacteria carried by circulating tumor cells promoted host-cell survival by enhancing resistance to fluid shear stress by reorganizing actin cytoskeleton. We further showed that intratumor administration of selected bacteria strains isolated from tumor-resident microbiota promoted metastasis in two murine tumor models with significantly different levels of metastasis potential. Our findings suggest that tumor-resident microbiota, albeit at low biomass, play an important role in promoting cancer metastasis, intervention of which might therefore be worth exploring for advancing oncology care.
    Keywords:  breast cancer metastasis; circulating tumor cells; cytoskeleton reorganization; fluid shear stress; intracellular bacteria; intratumor microbiota; metastatic colonization
  12. Cell Rep. 2022 Apr 05. pii: S2211-1247(22)00355-2. [Epub ahead of print]39(1): 110607
      The mechanism by which redox metabolism regulates the fates of acute myeloid leukemia (AML) cells remains largely unknown. Using a highly sensitive, genetically encoded fluorescent sensor of nicotinamide adenine dinucleotide phosphate (NADPH), iNap1, we find three heterogeneous subpopulations of AML cells with different cytosolic NADPH levels in an MLL-AF9-induced murine AML model. The iNap1-high AML cells have enhanced proliferation capacities both in vitro and in vivo and are enriched for more functional leukemia-initiating cells than iNap1-low counterparts. The iNap1-high AML cells prefer localizing in the bone marrow endosteal niche and are resistant to methotrexate treatment. Furthermore, iNap1-high human primary AML cells have enhanced proliferation abilities both in vitro and in vivo. Mechanistically, the MTHFD1-mediated folate cycle regulates NADPH homeostasis to promote leukemogenesis and methotrexate resistance. These results provide important clues for understanding mechanisms by which redox metabolism regulates cancer cell fates and a potential metabolic target for AML treatments.
    Keywords:  CP: Cancer; NADPH metabolism; acute myeloid leukemia; endosteal niche; folate cycle; leukemia-initiating cells; metabolic sensor; methotrexate resistance; methylenetetrahydrofolate dehydrogenase; tetrahydrofolic acid; vascular niche
  13. Trends Cancer. 2022 Mar 31. pii: S2405-8033(22)00069-3. [Epub ahead of print]
      As one of the deadliest cancers, pancreatic ductal adenocarcinoma (PDAC) requires sophisticated model systems to dissect disease onset, progression, and therapy resistance, as well as to personalize therapy. In recent years, patient- and pluripotent stem cell-derived organoids have become state-of-the-art systems to refine existing therapeutic strategies and deepen our knowledge of disease pathophysiology.
    Keywords:  organoids; pancreatic cancer; personalized medicine; stem cells