bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒12‒12
twelve papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Commun. 2021 Dec 06. 12(1): 7041
      Despite unprecedented responses of some cancers to immune checkpoint blockade (ICB) therapies, the application of checkpoint inhibitors in pancreatic cancer has been unsuccessful. Glucocorticoids and glucocorticoid receptor (GR) signaling are long thought to suppress immunity by acting on immune cells. Here we demonstrate a previously undescribed tumor cell-intrinsic role for GR in activating PD-L1 expression and repressing the major histocompatibility complex class I (MHC-I) expression in pancreatic ductal adenocarcinoma (PDAC) cells through transcriptional regulation. In mouse models of PDAC, either tumor cell-specific depletion or pharmacologic inhibition of GR leads to PD-L1 downregulation and MHC-I upregulation in tumor cells, which in turn promotes the infiltration and activity of cytotoxic T cells, enhances anti-tumor immunity, and overcomes resistance to ICB therapy. In patients with PDAC, GR expression correlates with high PD-L1 expression, low MHC-I expression, and poor survival. Our results reveal GR signaling in cancer cells as a tumor-intrinsic mechanism of immunosuppression and suggest that therapeutic targeting of GR is a promising way to sensitize pancreatic cancer to immunotherapy.
  2. Trends Cancer. 2021 Dec 03. pii: S2405-8033(21)00228-4. [Epub ahead of print]
      Metastasis is an evolutionary process occurring across multiple organs and timescales. Due to its continuous and dynamic nature, this multifaceted process has been challenging to investigate and remains incompletely understood, in part due to the lack of tools capable of probing genomic evolution at high enough resolution. However, technological advances in genetic sequencing and editing have provided new and powerful methods to refine our understanding of the complex series of events that lead to metastatic dissemination. In this review, we summarize the latest genetic and lineage-tracing approaches developed to unravel the genetic evolution of metastasis. The findings that have emerged have enhanced our comprehension of the mechanistic trajectories and timescales of metastasis and could provide new strategies for therapy.
    Keywords:  evolution; lineage tracing; metastasis; sequencing; single cell
  3. Cancer Discov. 2021 Dec 09.
      Genomically guided targeted therapy can improve progression-free survival for patients with metastatic breast cancer whose tumors bear mutations known to be sensitive to targeted therapies.
  4. Cell. 2021 Dec 09. pii: S0092-8674(21)01332-5. [Epub ahead of print]184(25): 6119-6137.e26
      Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.
    Keywords:  liver metastases; pancreatic cancer; patient-derived organoid models; plasticity; single-cell RNA-sequencing; transcriptional states; tumor heterogeneity; tumor microenvironment
  5. Autophagy. 2021 Dec 06. 1-19
      Acquired chemotherapy resistance is one of the main culprits in the relapse of breast cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small adaptor protein, SH3BGRL, is not only elevated in the majority of breast cancer patients but also has relevance with the relapse and poor prognosis of breast cancer patients. Functionally, SH3BGRL upregulation enhances the chemoresistance of breast cancer cells to the first-line doxorubicin treatment through macroautophagic/autophagic protection. Mechanistically, SH3BGRL can unexpectedly bind to ribosomal subunits to enhance PIK3C3 translation efficiency and sustain ATG12 stability. Therefore, inhibition of autophagy or silence of PIK3C3 or ATG12 can effectively block the driving effect of SH3BGRL on doxorubicin resistance of breast cancer cells in vitro and in vivo. We also validate that SH3BGRL expression is positively correlated with that of PIK3C3 or ATG12, as well as the constitutive occurrence of autophagy in clinical breast cancer tissues. Taken together, our data reveal that SH3BGRL upregulation would be a key driver to the acquired chemotherapy resistance through autophagy enhancement in breast cancer while targeting SH3BGRL could be a potential therapeutic strategy against breast cancer.
    Keywords:  ATG12; PIK3C3; SH3BGRL; autophagy; breast cancer; doxorubicin chemoresistance; polyribosome profile; protein stability; ribosome-binding protein
  6. Dev Cell. 2021 12 06. pii: S1534-5807(21)00897-2. [Epub ahead of print]56(23): 3174-3176
      In this issue of Developmental Cell, Lüönd et al. developed a tracing system, using the uncharacterized early epithelial-mesenchymal transition (EMT)-marker Tenascin C, to monitor cells undergoing partial EMT during malignant mammary cancer progression. They find that partial, but not full, EMT contributes to metastasis and that full EMT contributes to chemoresistance.
  7. Cell Metab. 2021 Dec 07. pii: S1550-4131(21)00539-8. [Epub ahead of print]33(12): 2380-2397.e9
      Accelerated glycolysis is the main metabolic change observed in cancer, but the underlying molecular mechanisms and their role in cancer progression remain poorly understood. Here, we show that the deletion of the long noncoding RNA (lncRNA) Neat1 in MMTV-PyVT mice profoundly impairs tumor initiation, growth, and metastasis, specifically switching off the penultimate step of glycolysis. Mechanistically, NEAT1 directly binds and forms a scaffold bridge for the assembly of PGK1/PGAM1/ENO1 complexes and thereby promotes substrate channeling for high and efficient glycolysis. Notably, NEAT1 is upregulated in cancer patients and correlates with high levels of these complexes, and genetic and pharmacological blockade of penultimate glycolysis ablates NEAT1-dependent tumorigenesis. Finally, we demonstrate that Pinin mediates glucose-stimulated nuclear export of NEAT1, through which it exerts isoform-specific and paraspeckle-independent functions. These findings establish a direct role for NEAT1 in regulating tumor metabolism, provide new insights into the Warburg effect, and identify potential targets for therapy.
    Keywords:  ENO1; NEAT1; PGAM1; PGK1; Pinin; Warburg effect; aerobic glycolysis; breast cancer; long noncoding RNA; tumor metabolism
  8. J Natl Cancer Inst. 2021 Dec 10. pii: djab222. [Epub ahead of print]
      BACKGROUND: N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies including breast cancer yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.METHODS: To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariate Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided.
    RESULTS: We generated new sublines that exhibit a distinct propensity to metastasize to the brain. NDRG1-high expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines, P = .01, Fisher's exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [CI] = 1.20 to 4.29, P = .009) and breast cancer-specific survival (HR = 2.19, 95% CI = 1.07 to 4.48, P = .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17; 95% CI = 1.10 to 4.30; P = .03) and breast cancer-specific survival rates (HR = 2.27; 95% CI = 1.05 to 4.92; P = .04).
    CONCLUSIONS: We demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.
  9. Cancer Res. 2021 Dec 06. pii: canres.0799.2021. [Epub ahead of print]
      Optimal treatment of cancer requires diagnostic methods to facilitate therapy choice and prevent ineffective treatments. Direct assessment of therapy response in viable tumor specimens could fill this diagnostic gap. Therefore, we designed a microfluidic platform for assessment of patient treatment response using tumor tissue slices under precisely controlled growth conditions. The optimized Cancer-on-Chip (CoC) platform maintained viability and sustained proliferation of breast and prostate tumor slices for 7 days. No major changes in tissue morphology or gene expression patterns were observed within this time frame, suggesting that the CoC system provides a reliable and effective way to probe intrinsic chemotherapeutic sensitivity of tumors. The customized CoC platform accurately predicted cisplatin and apalutamide treatment response in breast and prostate tumor xenograft models, respectively. The culture period for breast cancer could be extended up to 14 days without major changes in tissue morphology and viability. These culture characteristics enable assessment of treatment outcomes and open possibilities for detailed mechanistic studies.
  10. Mol Cancer. 2021 Dec 10. 20(1): 162
      BACKGROUND: Cis-diamminedichloro-platinum (CDDP)-based chemotherapy regimens are the most predominant treatment strategies for patients with esophageal squamous cell carcinoma (ESCC). Dysregulated long non-coding RNAs (lncRNAs) contribute to CDDP resistance, which results in treatment failure in ESCC patients. However, the majority of lncRNAs involved in CDDP resistance in ESCC remain to be elucidated.METHODS: The public Gene Expression Omnibus (GEO) dataset GSE45670 was analysed to reveal potential lncRNAs involved in CDDP resistance of ESCC. Candidate upregulated lncRNAs were detected in ESCC specimens by qRT-PCR to identify crucial lncRNAs. Non-coding RNA activated by DNA damage (NORAD) was selected for further study. Kaplan-Meier analysis and a COX proportional regression model were performed to analyse the potential of NORAD for predicting prognosis of ESCC patients. The role of NORAD in CDDP resistance were determined by conducting gain and loss-of-function experiments in vitro. Fluorescence in situ hybridization (FISH) was performed to determine the subcellular location of NORAD in ESCC cells. A public GEO dataset and bioinformatic algorithms were used to predict the microRNAs (miRNAs) that might be latently sponged by NORAD. qRT-PCR was conducted to verify the expression of candidate miRNAs. Luciferase reporter and Argonaute-2 (Ago2)-RNA immunoprecipitation (RIP) assays were conducted to evaluate the interaction between NORAD and candidate miRNAs. A miRNA rescue experiment was performed to authenticate the NORAD regulatory axis and its effects on CDDP resistance in ESCC cells. Western blotting was conducted to confirm the precise downstream signalling pathway of NORAD. A xenograft mouse model was established to reveal the effect of NORAD on CDDP resistance in vivo.
    RESULTS: The expression of NORAD was higher in CDDP-resistant ESCC tissues and cells than in CDDP-sensitive tissues and cells. NORAD expression was negatively correlated with the postoperative prognosis of ESCC patients who underwent CDDP-based chemotherapy. NORAD knockdown partially arrested CDDP resistance of ESCC cells. FISH showed that NORAD was located in the cytoplasm in ESCC cells. Furthermore, overlapping results from bioinformatic algorithms analyses and qRT-PCR showed that NORAD could sponge miR-224-3p in ESCC cells. Ago2-RIP demonstrated that NORAD and miR-224-3p occupied the same Ago2 to form an RNA-induced silencing complex (RISC) and subsequently regulated the expression of metadherin (MTDH) in ESCC cells. The NORAD/miR-224-3p/MTDH axis promoted CDDP resistance and progression in ESCC cells by promoting nuclear accumulation of β-catenin in vitro and in vivo.
    CONCLUSIONS: NORAD upregulates MTDH to promote CDDP resistance and progression in ESCC by sponging miR-224-3p. Our results highlight the potential of NORAD as a therapeutic target in ESCC patients receiving CDDP-based chemotherapy.
    Keywords:  CDDP resistance; ESCC; MTDH; NORAD; miR-224-3p
  11. Nucleic Acids Res. 2021 Dec 02. 49(21): 12211-12233
      Subunits of the chromatin remodeler SWI/SNF are the most frequently disrupted genes in cancer. However, how post-translational modifications (PTM) of SWI/SNF subunits elicit epigenetic dysfunction remains unknown. Arginine-methylation of BAF155 by coactivator-associated arginine methyltransferase 1 (CARM1) promotes triple-negative breast cancer (TNBC) metastasis. Herein, we discovered the dual roles of methylated-BAF155 (me-BAF155) in promoting tumor metastasis: activation of super-enhancer-addicted oncogenes by recruiting BRD4, and repression of interferon α/γ pathway genes to suppress host immune response. Pharmacological inhibition of CARM1 and BAF155 methylation not only abrogated the expression of an array of oncogenes, but also boosted host immune responses by enhancing the activity and tumor infiltration of cytotoxic T cells. Moreover, strong me-BAF155 staining was detected in circulating tumor cells from metastatic cancer patients. Despite low cytotoxicity, CARM1 inhibitors strongly inhibited TNBC cell migration in vitro, and growth and metastasis in vivo. These findings illustrate a unique mechanism of arginine methylation of a SWI/SNF subunit that drives epigenetic dysregulation, and establishes me-BAF155 as a therapeutic target to enhance immunotherapy efficacy.
  12. Mol Cancer. 2021 Dec 07. 20(1): 161
      BACKGROUND: Circular RNAs (circRNAs), a class of noncoding RNAs (ncRNAs), may modulate gene expression by binding to miRNAs. Additionally, recent studies show that circRNAs participate in some pathological processes. However, there is a large gap in the knowledge about circDOCK1 expression and its biological functions in osteogenic sarcoma (OS).METHODS: Differentially expressed circRNAs in OS cell lines and tissues were identified by circRNA microarray analysis and quantitative real-time PCR (qRT-PCR). To explore the actions of circDOCK1 in vivo and in vitro, circDOCK1 was knocked down or overexpressed. To assess the binding and regulatory associations among miR-339-3p, circDOCK1 and IGF1R, we performed rescue experiments, RNA immunoprecipitation (RIP), RNA pulldown assays and dual-luciferase assays. Moreover, we performed apoptosis assays to reveal the regulatory effects of the circDOCK1/miR-339-3p/IGF1R axis on cisplatin sensitivity.
    RESULTS: CircDOCK1 expression remained stable in the cytoplasm and was higher in OS tissues and cells than in the corresponding controls. Overexpression of circDOCK1 increased oncogenicity in vivo and malignant transformation in vitro. In the U2OS and MG63 cell lines, circDOCK1 modulated tumor progression by regulating IGF1R through sponging of miR-339-3p. Additionally, in the U2OS/DDP and MG63/DDP cell lines, cisplatin sensitivity was regulated by circDOCK1 via the miR-339-3p/IGF1R axis.
    CONCLUSIONS: CircDOCK1 can promote progression and regulate cisplatin sensitivity in OS via the miR-339-3p/IGF1R axis. Thus, the circDOCK1/miR-339-3p/IGF1R axis may be a key mechanism and therapeutic target in OS.
    Keywords:  Cisplatin resistance; IGF1R; OS; circDOCK1; miR-339-3p