bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒08‒15
twenty-two papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Discov. 2020 Aug;10(8): 1089
      A liquid biopsy-based method, dubbed EV-CLUE, discerned breast cancer invasiveness and metastasis.
  2. Cancer Discov. 2020 Dec;10(12): OF9
      Lung mesenchymal cells promoted neutrophil lipid storage; lipids were transferred to tumor cells.
  3. Cancer Discov. 2020 Jul;10(7): 903
      Whether metastases were seeded mono- or polyclonally depended on cancer site and treatment.
  4. Cancer Discov. 2020 Jan;10(1): 13
      Anti-CTLA4 caused Th1 expansion in primary prostate-cancer tumors, but not bone metastases.
  5. Cancer Cell. 2021 Aug 09. pii: S1535-6108(21)00390-1. [Epub ahead of print]39(8): 1047-1049
      Resistance to targeted therapies is a major challenge in cancer care and occurs via genetic and non-genetic mechanisms. In this issue of Cancer Cell, Marin-Bejar et al. demonstrate that melanomas recurrently select genetic or non-genetic resistance trajectories and that targeting neural crest stem cell-like cells prevents non-genetic, but not genetic, resistance.
  6. Cancer Discov. 2020 Nov;10(11): 1621
      Lymphatic melanoma cells had less ferroptosis than cells injected intravenously or subcutaneously.
  7. Cancer Discov. 2020 Aug;10(8): OF12
      DNA-protein complexes called neutrophil extracellular traps were chemoattractants for metastatic cells.
  8. Nature. 2021 Aug 11.
      Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell's clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.
  9. Cancer Discov. 2020 Aug;10(8): 1090
      The small-molecule tyrosine kinase inhibitor tucatinib outperformed placebo against brain metastases.
  10. Cancer Discov. 2020 Oct;10(10): OF5
      New androgen receptor binding sites acquired with metastasis overlapped with those in fetal tissue.
  11. Cancer Res. 2021 Aug 12. pii: canres.3982.2020. [Epub ahead of print]
      Collagen remodeling contributes to many physiological and pathological processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that WISP2 expression is lower in most solid tumors, in comparison to normal tissues. Consequently, genetic or pharmacological restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in vivo in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2:WISP1 ratio.
  12. Cancer Cell. 2021 Jul 27. pii: S1535-6108(21)00383-4. [Epub ahead of print]
      The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by the eventual development of acquired resistance. We hypothesize that enhancing apoptosis through combination therapies can eradicate cancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughput screening of a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibition stabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivity to respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but also overcomes resistance beyond EMT.
    Keywords:  Aurora B kinase; BCL-2 family; EMT; apoptosis; drug resistance; drug tolerance; epidermal growth factor receptor; lineage plasticity; lung cancer; mitotic catastrophe
  13. Theranostics. 2021 ;11(17): 8218-8233
      Purpose: Functional loss of BRCA1 is associated with poorly differentiated and metastatic breast cancers that are enriched with cancer stem cells (CSCs). CSCs can be generated from carcinoma cells through an epithelial-mesenchymal transition (EMT) program. We and others have previously demonstrated that BRCA1 suppresses EMT and regulates the expression of multiple EMT-related transcription factors. However, the downstream mediators of BRCA1 function in EMT suppression remain elusive. Methods: Depletion of BRCA1 or GATA3 activates p18INK4C , a cell cycle inhibitor which inhibits mammary epithelial cell proliferation. We have therefore created genetically engineered mice with Brca1 or Gata3 loss in addition to deletion of p18INK4C , to rescue proliferative defects caused by deficiency of Brca1 or Gata3. By using these mutant mice along with human BRCA1 deficient as well as proficient breast cancer tissues and cells, we investigated and compared the role of Brca1 and Gata3 loss in the activation of EMT in breast cancers. Results: We discovered that BRCA1 and GATA3 expressions were positively correlated in human breast cancer. Depletion of BRCA1 stimulated methylation of GATA3 promoter thereby repressing GATA3 transcription. We developed Brca1 and Gata3 deficient mouse system. We found that Gata3 deficiency in mice induced poorly-differentiated mammary tumors with the activation of EMT and promoted tumor initiating and metastatic potential. Gata3 deficient mammary tumors phenocopied Brca1 deficient tumors in the induction of EMT under the same genetic background. Reconstitution of Gata3 in Brca1-deficient tumor cells activated mesenchymal-epithelial transition, suppressing tumor initiation and metastasis. Conclusions: Our finding, for the first time, demonstrates that GATA3 functions downstream of BRCA1 to suppress EMT in controlling mammary tumorigenesis and metastasis.
    Keywords:  BRCA1; EMT; GATA3; metastasis; tumorigenesis
  14. Cancer Discov. 2020 Dec;10(12): 1784
      Endothelial cell-produced SLIT2 drove tumor-cell migration to blood vessels to promote metastasis.
  15. Cancer Discov. 2020 Jan;10(1): OF3
      Colorectal cancer cells react to targeted therapies by transiently increasing their mutation rate.
  16. Nat Commun. 2021 08 10. 12(1): 4803
      Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs.
  17. Nat Commun. 2021 08 11. 12(1): 4867
      Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.
  18. Nat Commun. 2021 08 11. 12(1): 4853
      SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3'UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
  19. Nat Commun. 2021 08 10. 12(1): 4840
      Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies.
  20. Nature. 2021 Aug 11.
    Keywords:  Cancer; Medical research; Metabolism
  21. Cancer Res. 2021 Aug 13. pii: canres.0101.2021. [Epub ahead of print]
      While macrophages are among the most abundant immune cell type found within primary and metastatic mammary tumors, how their complexity and heterogeneity change with metastatic progression remains unknown. Here, macrophages were isolated from the lungs of mice bearing orthotopic mammary tumors for single-cell RNA sequencing. Seven distinct macrophage clusters were identified, including populations exhibiting enhanced differential expression of genes related to antigen presentation (H2-Aa, Cd74), cell cycle (Stmn1, Cdk1), and interferon signaling (Isg15, Ifitm3). Interestingly, one cluster demonstrated a profile concordant with lipid-associated macrophages (Lgals3, Trem2). Compared to non-tumor-bearing controls, the number of these cells per gram of tissue was significantly increased in lungs from tumor-bearing mice, with the vast majority co-staining positively with the alveolar macrophage marker Siglec-F. Enrichment of genes implicated in pathways related to lipid metabolism as well extracellular matrix remodeling and immunosuppression was observed. Additionally, these cells displayed reduced capacity for phagocytosis. Collectively, these findings highlight the diversity of macrophages present within metastatic lesions and characterize a lipid-associated macrophage subset previously unidentified in lung metastases.
  22. Proc Natl Acad Sci U S A. 2021 Aug 17. pii: e2012881118. [Epub ahead of print]118(33):
      Circular RNAs (circRNAs) have emerged as key regulators of human cancers, yet their modes of action in gastric cancer (GC) remain largely unknown. Here, we identified circURI1 back-spliced from exons 3 and 4 of unconventional prefoldin RPB5 interactor 1 (URI1) from circRNA profiling of five-paired human gastric and the corresponding nontumor adjacent specimens (paraGC). CircURI1 exhibits the significantly higher expression in GC compared with paraGC and inhibitory effects on cell migration and invasion in vitro and GC metastasis in vivo. Mechanistically, circURI1 directly interacts with heterogeneous nuclear ribonucleoprotein M (hnRNPM) to modulate alternative splicing of genes, involved in the process of cell migration, thus suppressing GC metastasis. Collectively, our study expands the current knowledge regarding the molecular mechanism of circRNA-mediated cancer metastasis via modulating alternative splicing.
    Keywords:  alternative splicing; circURI1; gastric cancer; hnRNPM; metastasis