bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒11‒21
nineteen papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Nat Commun. 2021 Nov 18. 12(1): 6692
      Metastatic cancer is associated with poor patient prognosis but its spatiotemporal behavior remains unpredictable at early stage. Here we develop MetaNet, a computational framework that integrates clinical and sequencing data from 32,176 primary and metastatic cancer cases, to assess metastatic risks of primary tumors. MetaNet achieves high accuracy in distinguishing the metastasis from the primary in breast and prostate cancers. From the prediction, we identify Metastasis-Featuring Primary (MFP) tumors, a subset of primary tumors with genomic features enriched in metastasis and demonstrate their higher metastatic risk and shorter disease-free survival. In addition, we identify genomic alterations associated with organ-specific metastases and employ them to stratify patients into various risk groups with propensities toward different metastatic organs. This organotropic stratification method achieves better prognostic value than the standard histological grading system in prostate cancer, especially in the identification of Bone-MFP and Liver-MFP subtypes, with potential in informing organ-specific examinations in follow-ups.
  2. Nat Commun. 2021 Nov 18. 12(1): 6667
      Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.
  3. Oncogene. 2021 Nov 15.
      The molecular and cellular mechanisms underlying mammary tumour dormancy and cancer recurrence are unclear and remain to be elucidated. Here, we report that mammary epithelial-specific disruption of β1 integrin in a murine model of Luminal B human breast cancer drastically impairs tumour growth with proliferation block, apoptosis induction and cellular senescence. β1 integrin-deficient dormant lesions show activation of the tumour suppressor p53, and tumours that circumvent dormancy possess p53 mutation analogous to those in human disease. We further demonstrate that mammary epithelial deletion of p53 in β1 integrin-deficient mice fully rescues tumour dormancy and bypasses cellular senescence. Additionally, recurrent β1 integrin-deficient tumours exhibit fibrosis with increased cancer-associated fibroblast infiltration and extracellular matrix deposition, absent in fast-growing β1 integrin/p53-deficient lesions. Taken together, these observations argue that β1 integrin modulates p53-dependent cellular senescence resulting in tumour dormancy and that pro-tumourigenic stromal cues and intrinsic genetic mutation are required for dormancy exit.
  4. Cancer Discov. 2021 Nov 19.
      KRAS(G12C) inhibitor (G12Ci) resistance exhibits a heterogeneous pattern with no one dominant alteration.
  5. Cell Rep. 2021 Nov 16. pii: S2211-1247(21)01509-6. [Epub ahead of print]37(7): 110027
      Early steps of cancer initiation and metastasis, while critical for understanding disease mechanisms, are difficult to visualize and study. Here, we describe an approach to study the processes of initiation, progression, and metastasis of prostate cancer (PC) in a genetically engineered RapidCaP mouse model, which combines whole-organ imaging by serial two-photon tomography (STPT) and post hoc thick-section immunofluorescent (IF) analysis. STPT enables the detection of single tumor-initiating cells within the entire prostate, and consequent IF analysis reveals a transition from normal to transformed epithelial tissue and cell escape from the tumor focus. STPT imaging of the liver and brain reveal the distribution of multiple metastatic foci in the liver and an early-stage metastatic cell invasion in the brain. This imaging and data analysis pipeline can be readily applied to other mouse models of cancer, offering a highly versatile whole-organ platform to study in situ mechanisms of cancer initiation and progression.
    Keywords:  early metastasis; prostate cancer; serial two-photon tomography; single-cell resolution; whole-organ imaging
  6. Oncogene. 2021 Nov 17.
      CHD5, a tumor suppressor at 1p36, is frequently lost or silenced in poor prognosis neuroblastoma (NB) and many adult cancers. The role of CHD5 in metastasis is unknown. We confirm that low expression of CHD5 is associated with stage 4 NB. Forced expression of CHD5 in NB cell lines with 1p loss inhibited key aspects of the metastatic cascade in vitro: anchorage-independent growth, migration, and invasion. In vivo, formation of bone marrow and liver metastases developing from intravenously injected NB cells was delayed and decreased by forced CHD5 expression. Genome-wide mRNA sequencing revealed reduction of genes and gene sets associated with metastasis when CHD5 was overexpressed. Known metastasis-suppressing genes preferentially upregulated in CHD5-overexpressing NB cells included PLCL1. In patient NB, low expression of PLCL1was associated with metastatic disease and poor survival. Knockdown of PLCL1 and of p53 in IMR5 NB cells overexpressing CHD5 reversed CHD5-induced inhibition of invasion and migration in vitro. In summary, CHD5 is a metastasis suppressor in NB.
  7. Nat Commun. 2021 Nov 18. 12(1): 6742
      Immunotherapy has become a powerful cancer treatment, but only a small fraction of patients have achieved durable benefits due to the immune escape mechanism. In this study, epigenetic regulation is combined with gene therapy-mediated immune checkpoint blockade to relieve this immune escape mechanism. PPD (i.e., mPEG-b-PLG/PEI-RT3/DNA) is developed to mediate plasmid-encoding shPD-L1 delivery by introducing multiple interactions (i.e., electrostatic, hydrogen bonding, and hydrophobic interactions) and polyproline II (PPII)-helix conformation, which downregulates PD-L1 expression on tumour cells to relieve the immunosuppression of T cells. Zebularine (abbreviated as Zeb), a DNA methyltransferase inhibitor (DNMTi), is used for the epigenetic regulation of the tumour immune microenvironment, thus inducing DC maturation and MHC I molecule expression to enhance antigen presentation. PPD plus Zeb combination therapy initiates a systemic anti-tumour immune response and effectively prevents tumour relapse and metastasis by generating durable immune memory. This strategy provides a scheme for tumour treatment and the inhibition of relapse and metastasis.
  8. Oncogene. 2021 Nov 19.
      Emerging evidence shows the association between nuclear envelope and tumor progression, however, the functional contributions of specific constituents of the nuclear envelope remain largely unclear. We found that the expression level of transmembrane protein 201 (TMEM201), an integral inner nuclear membrane protein of unknown function, was significantly elevated in invasive breast cancer and predicted poor breast cancer prognosis. We showed that TMEM201, as a positive modulator, was both necessary and sufficient to regulate the migration and invasion of breast cancer cells in vitro and in vivo. Mechanistically, RNA-sequencing analysis and validation showed that TMEM201 deficiency inhibited epithelial-to-mesenchymal transition and transforming growth factor-β signaling. Finally, we showed that TMEM201 physically interacted with SMAD2/3 and was required for the phosphorylation of SMAD2/3, nuclear translocation and transcriptional activation of the TGFβ. Thus, we demonstrated that specific inner nuclear membrane component mediated signal-dependent transcriptional effects to control breast cancer metastasis.
  9. Nat Commun. 2021 Nov 18. 12(1): 6738
      FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.
  10. EMBO Rep. 2021 Nov 15. e53054
      Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.
    Keywords:  CRISPR-Cas9 screen; cancer; chemoresistance; inhibitor of mitochondrial transcription; mtDNA
  11. Proc Natl Acad Sci U S A. 2021 Nov 23. pii: e2112674118. [Epub ahead of print]118(47):
      High expression of programmed death-ligand 1 (PD-L1) in cancer cells drives immune-independent, cell-intrinsic functions, leading to resistance to DNA-damaging therapies. We find that high expression of the ubiquitin E3 ligase FBXO22 sensitizes nonsmall cell lung cancer (NSCLC) cells to ionizing radiation (IR) and cisplatin, and that activation of FBXO22 by phosphorylation is necessary for this function. Importantly, FBXO22 activates PD-L1 ubiquitination and degradation, which in turn increases the sensitivity of NSCLC cells to DNA damage. Cyclin-dependent kinase 5 (CDK5), aberrantly active in cancer cells, plays a crucial role in increasing the expression of PD-L1 in medulloblastoma [R. D. Dorand et al, Science 353, 399-403 (2016)]. We show in NSCLC cells that inhibiting CDK5 or reducing its expression increases the level of FBXO22, decreases that of PD-L1, and increases the sensitivity of the cells to DNA damage. We conclude that FBXO22 is a substrate of CDK5, and that inhibiting CDK5 reduces PD-L1 indirectly by increasing FBXO22. Pairing inhibitors of CDK5 with immune checkpoint inhibitors may increase the efficacy of immune checkpoint blockade alone or in combination with DNA-damaging therapies.
    Keywords:  CDK5; FBXO22; PD-L1; lung cancer
  12. Cancer Res. 2021 Nov 15. 81(22): 5611-5612
      It is now well appreciated that the tumor microenvironment (TME) surrounding primary tumors impacts tumor growth, progression (invasion and migration), and response to therapy. Broadly speaking, the TME is composed of cells (immune cells, activated fibroblasts, adipocytes, endothelial cells), acellular extracellular matrix (ECM), and cytokines or growth factors, some of which are bound or tethered to the ECM proteins. All these compartments undergo significant changes during tumor development and progression. Changes to the ECM, in particular, can dramatically influence cancer biology. This has stimulated the development of therapies that directly reverse or prevent the structural changes in the TME ECM that facilitate cancer progression. But to do so, in a rational manner, we need to understand how structural changes to tumor ECM arise, are remodeled, and function to facilitate tumor cell invasion and migration that give rise to metastatic disease, which is the main cause of cancer-related deaths. In this issue of Cancer Research, Janjanam and colleagues show that the ratio of WISP1/WISP2 in tumors is critical for ECM collagen fiber linearization and important for metastasis. WISP2 binds ECM collagen directly and can inhibit WISP1-mediated collagen linearization. These new results offer a new approach for targeting the altered collagen ECM in tumors by preventing or reversing collagen linearization.See related article by Janjanam et al., p. 5666.
  13. J Clin Invest. 2021 Nov 15. pii: e145142. [Epub ahead of print]131(22):
      High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7-independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.
    Keywords:  Cancer; Cell migration/adhesion; Oncology; Translation
  14. J Clin Invest. 2021 Nov 15. pii: e144871. [Epub ahead of print]131(22):
      Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
    Keywords:  Angiogenesis; Breast cancer; Cancer; Metabolism
  15. EMBO Rep. 2021 Nov 15. e53140
      Oxaliplatin (L-OHP) is a standard treatment for colorectal cancer (CRC), but chemoresistance is a considerable challenge. L-OHP shows dose-dependent toxicity, and potential approaches that sensitize cancer cells to L-OHP could reduce the dosage. With the development of translatomics, it was found that some lncRNAs encode short peptides. Here, we use ribosome footprint profiling combined with lncRNA-Seq to screen 12 lncRNAs with coding potential, of which lnc-AP encodes the short peptide pep-AP, for their role in L-OHP resistance. Co-IP and LC-MS/MS data show that the TALDO1 protein interacts with pep-AP and that pep-AP suppresses the expression of TALDO1. The pep-AP/TALDO1 pathway attenuates the pentose phosphate pathway (PPP), reducing NADPH/NADP+ and glutathione (GSH) levels and causing ROS accumulation and apoptosis, which sensitizes CRC cells to L-OHP in vitro and in vivo. pep-AP thus might become a potential anticancer peptide for future treatments of L-OHP-resistant CRC.
    Keywords:  ROS; lncRNA; oxaliplatin resistance; pentose phosphate pathway; peptide
  16. Cancer Res. 2021 Nov 16. pii: canres.1940.2021. [Epub ahead of print]
      Heterogeneity is a pervasive feature of cancer, and understanding the sources and regulatory mechanisms underlying heterogeneity could provide key insights to help improve the diagnosis and treatment of cancer. In this review, we discuss the origin of heterogeneity in the phenotype of individual cancer cells. Genotype-phenotype (G-P) maps are widely used in evolutionary biology to represent the complex interactions of genes and the environment that lead to phenotypes that impact fitness. Here, we present the rationale of an extended G-P (eG-P) map with a cone structure in cancer. The eG-P cone is formed by cells that are similar at the genome layer but gradually increase variability in the epigenome, transcriptome, proteome, metabolome and signalome layers to produce large variability at the phenome layer. Experimental evidence from single-cell -omics analyses supporting the cancer eG-P cone concept is presented, and the impact of epimutations and the interaction of cancer and tumor microenvironmental eG-P cones are integrated with the current understanding of cancer biology. The eG-P cone concept uncovers potential therapeutic strategies to reduce cancer evolution and improve cancer treatment. More methods to study phenotypes in single cells will be key to better understand cancer cell fitness in tumor biology and therapeutics.