bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒07‒17
fifteen papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Metastatic Metabolic Plasticity Is Shaped by RNA Methylation Modifications.
  2. Persister cells that survive chemotherapy are pinpointed.
  3. A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells.
  4. Node foretold: Cancer cells in lymph node rewire the immune system to enable further metastases.
  5. FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma.
  6. Nocturnal habits of circulating tumor cells.
  7. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents.
  8. Gain of chromosome 1q perturbs a competitive endogenous RNA network to promote melanoma metastasis.
  9. N6-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming.
  10. Colorectal cancer cells expressing Mex3a drive recurrence after chemotherapy.
  11. Mapping the immune landscape in metastatic melanoma reveals localized cell-cell interactions that predict immunotherapy response.
  12. The oligometastatic spectrum in the era of improved detection and modern systemic therapy.
  13. Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells.
  14. CircBCAR3 accelerates esophageal cancer tumorigenesis and metastasis via sponging miR-27a-3p.
  15. Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1.
  1. Cancer Discov. 2022 Jul 15. OF1
    Metastatic Metabolic Plasticity Is Shaped by RNA Methylation Modifications.
      The m5c and f5c RNA modifications support mitochondrial mRNA translation promoting metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-126
  2. Nature. 2022 Jul 12.
    Persister cells that survive chemotherapy are pinpointed.
    Sumaiyah K Rehman, Catherine A O'Brien.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-022-01866-x
  3. Nat Genet. 2022 Jul;54(7): 976-984
    A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells.
    Mariangela Russo, Simone Pompei, Alberto Sogari, Mattia Corigliano, Giovanni Crisafulli, Alberto Puliafito, Simona Lamba, Jessica Erriquez, Andrea Bertotti, Marco Gherardi, Federica Di Nicolantonio, Alberto Bardelli, Marco Cosentino Lagomarsino.
      Compelling evidence shows that cancer persister cells represent a major limit to the long-term efficacy of targeted therapies. However, the phenotype and population dynamics of cancer persister cells remain unclear. We developed a quantitative framework to study persisters by combining experimental characterization and mathematical modeling. We found that, in colorectal cancer, a fraction of persisters slowly replicates. Clinically approved targeted therapies induce a switch to drug-tolerant persisters and a temporary 7- to 50-fold increase of their mutation rate, thus increasing the number of persister-derived resistant cells. These findings reveal that treatment may influence persistence and mutability in cancer cells and pinpoint inhibition of error-prone DNA polymerases as a strategy to restrict tumor recurrence.
    DOI:  https://doi.org/10.1038/s41588-022-01105-z
  4. Cancer Cell. 2022 Jul 07. pii: S1535-6108(22)00311-7. [Epub ahead of print]
    Node foretold: Cancer cells in lymph node rewire the immune system to enable further metastases.
    Hilda L Chan, Xiang H-F Zhang.
      A Cell article reports that lymph node metastases can suppress the immune system, thereby promoting further cancer spread in mouse models; this is corroborated in patients as described in a letter in this issue of Cancer Cell. The lymph node thus actively generates a cancer-permissive environment and is an untapped target to manipulate the immune system.
    DOI:  https://doi.org/10.1016/j.ccell.2022.07.001
  5. Dev Cell. 2022 Jul 05. pii: S1534-5807(22)00458-0. [Epub ahead of print]
    FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma.
    Grace Orstad, Gabriela Fort, Timothy J Parnell, Alex Jones, Chris Stubben, Brian Lohman, Katherine L Gillis, Walter Orellana, Rushmeen Tariq, Olaf Klingbeil, Klaus Kaestner, Christopher R Vakoc, Benjamin T Spike, Eric L Snyder.
      Changes in cellular identity (also known as histologic transformation or lineage plasticity) can drive malignant progression and resistance to therapy in many cancers, including lung adenocarcinoma (LUAD). The lineage-specifying transcription factors FoxA1 and FoxA2 (FoxA1/2) control identity in NKX2-1/TTF1-negative LUAD. However, their role in NKX2-1-positive LUAD has not been systematically investigated. We find that Foxa1/2 knockout severely impairs tumorigenesis in KRAS-driven genetically engineered mouse models and human cell lines. Loss of FoxA1/2 leads to the collapse of a dual-identity state, marked by co-expression of pulmonary and gastrointestinal transcriptional programs, which has been implicated in LUAD progression. Mechanistically, FoxA1/2 loss leads to aberrant NKX2-1 activity and genomic localization, which in turn actively inhibits tumorigenesis and drives alternative cellular identity programs that are associated with non-proliferative states. This work demonstrates that FoxA1/2 expression is a lineage-specific vulnerability in NKX2-1-positive LUAD and identifies mechanisms of response and resistance to targeting FoxA1/2 in this disease.
    Keywords:  FoxA1; FoxA2; NKX2-1; cellular identity; lineage switching; lung adenocarcinoma
    DOI:  https://doi.org/10.1016/j.devcel.2022.06.017
  6. Nat Med. 2022 Jul 11.
    Nocturnal habits of circulating tumor cells.
    Karen O'Leary.
      
    Keywords:  Breast cancer; Metastasis
    DOI:  https://doi.org/10.1038/d41591-022-00075-3
  7. Theranostics. 2022 ;12(11): 4935-4948
    Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents.
    Qingjuan Chen, Binhui Yang, Xiaochen Liu, Xu D Zhang, Lirong Zhang, Tao Liu.
      The histone acetyltransferases CBP and p300, often referred to as CBP/p300 due to their sequence homology and functional overlap and co-operation, are emerging as critical drivers of oncogenesis in the past several years. CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super-enhancers, thereby activating gene transcription. While earlier studies indicate that CBP/p300 deletion/loss can promote tumorigenesis, CBP/p300 have more recently been shown to be over-expressed in cancer cells and drug-resistant cancer cells, activate oncogene transcription and induce cancer cell proliferation, survival, tumorigenesis, metastasis, immune evasion and drug-resistance. Small molecule CBP/p300 histone acetyltransferase inhibitors, bromodomain inhibitors, CBP/p300 and BET bromodomain dual inhibitors and p300 protein degraders have recently been discovered. The CBP/p300 inhibitors and degraders reduce H3K27ac, down-regulate oncogene transcription, induce cancer cell growth inhibition and cell death, activate immune response, overcome drug resistance and suppress tumor progression in vivo. In addition, CBP/p300 inhibitors enhance the anticancer efficacy of chemotherapy, radiotherapy and epigenetic anticancer agents, including BET bromodomain inhibitors; and the combination therapies exert substantial anticancer effects in mouse models of human cancers including drug-resistant cancers. Currently, two CBP/p300 inhibitors are under clinical evaluation in patients with advanced and drug-resistant solid tumors or hematological malignancies. In summary, CBP/p300 have recently been identified as critical tumorigenic drivers, and CBP/p300 inhibitors and protein degraders are emerging as promising novel anticancer agents for clinical translation.
    Keywords:  CBP/p300; cancer therapy; gene transcription; small molecule inhibitors; tumorigenesis
    DOI:  https://doi.org/10.7150/thno.73223
  8. Cancer Res. 2022 Aug 31. pii: can.22.0283. [Epub ahead of print]
    Gain of chromosome 1q perturbs a competitive endogenous RNA network to promote melanoma metastasis.
    Xiaonan Xu, Kaizhen Wang, Olga Vera, Akanksha Verma, Neel Jasani, Ilah Bok, Olivier Elemento, Dongliang Du, Xiaoqing Yu, Florian A Karreth.
      Somatic copy number alterations (CNA) promote cancer, but the underlying driver genes may not be comprehensively identified if only the functions of the encoded proteins are considered. mRNAs can act as competitive endogenous RNAs (ceRNA) that sponge miRNAs to post-transcriptionally regulate gene expression in a protein coding-independent manner. We investigated the contribution of ceRNAs to the oncogenic effects of CNAs. Chromosome 1q gains promoted melanoma progression and metastasis at least in part through overexpression of three mRNAs with ceRNA activity: CEP170, NUCKS1, and ZC3H11A. These ceRNAs enhanced melanoma metastasis by sequestering tumor suppressor miRNAs. Orthogonal genetic assays with miRNA inhibitors and target site blockers, along with rescue experiments, demonstrated that miRNA sequestration is critical for the oncogenic effects of CEP170, NUCKS1, and ZC3H11A mRNAs. Furthermore, chromosome 1q ceRNA-mediated miRNA sequestration alleviated the repression of several pro-metastatic target genes. This regulatory RNA network was evident in other cancer types, suggesting chromosome 1q ceRNA deregulation as a common driver of cancer progression. Taken together, this work demonstrates that ceRNAs mediate the oncogenicity of somatic CNAs.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0283
  9. Theranostics. 2022 ;12(10): 4802-4817
    N6-methyladenosine-mediated LDHA induction potentiates chemoresistance of colorectal cancer cells through metabolic reprogramming.
    Kun Zhang, Tao Zhang, Yuhan Yang, Wenling Tu, Hongbin Huang, Yujun Wang, Yuzhuo Chen, Kejian Pan, Zhuojia Chen.
      Background: Chemoresistance to 5-fluorouracil (5-FU) is a major barrier to influence the treatment efficiency of colorectal cancer (CRC) patients, while the precise molecular mechanisms underlying 5-FU resistance remain to be fully elucidated. Methods: The metabolic profiles including ATP generation, glucose consumption, lactate generation, and oxygen consumption rate (OCR) in 5-FU resistant CRC cells were compared with those in their parental cells. Subsequently, a series of in vitro and in vivo experiments were carried out to investigate the mechanisms responsible for metabolic reprogramming of 5-FU resistant CRC cells. Results: We found that 5-FU resistant CRC cells showed increased levels of ATP generation, glucose consumption, lactate generation, and OCR as compared with those in their parental cells. Further, increased levels of mRNA N6-methyladenosine (m6A) and methyltransferase-like 3 (METTL3) were observed in 5-FU resistant CRC cells. Inhibition or knockdown of METTL3 can suppress glycolysis and restore chemosensitivity of 5-FU resistant CRC cells. Mechanistically, METTL3 enhances the expression of LDHA, which catalyzes the conversion of pyruvate to lactate, to trigger glycolysis and 5-FU resistance. METTL3 can increase the transcription of LDHA via stabilizing mRNA of hypoxia-inducible factor (HIF-1α), further, METTL3 also triggers the translation of LDHA mRNA via methylation of its CDS region and recruitment of YTH domain-containing family protein 1 (YTHDF1). Targeted inhibition of METTL3/LDHA axis can significantly increase the in vitro and in vivo 5-FU sensitivity of CRC cells. Conclusion: Our study indicates that METTL3/LDHA axis-induced glucose metabolism is a potential therapy target to overcome 5-FU resistance in CRC cells.
    Keywords:  5-FU; Chemoresistance; Glycolysis; LDHA; METTL3
    DOI:  https://doi.org/10.7150/thno.73746
  10. Nat Cancer. 2022 Jul 13.
    Colorectal cancer cells expressing Mex3a drive recurrence after chemotherapy.
      
    DOI:  https://doi.org/10.1038/s43018-022-00409-7
  11. Cancer Res. 2022 Jul 14. pii: can.22.0363. [Epub ahead of print]
    Mapping the immune landscape in metastatic melanoma reveals localized cell-cell interactions that predict immunotherapy response.
    Asier Antoranz, Yannick Van Herck, Maddalena M Bolognesi, Seodhna M Lynch, Arman Rahman, William M Gallagher, Veerle Boecxstaens, Jean-Christophe Marine, Giorgio Cattoretti, Joost J van den Oord, Frederik De Smet, Oliver Bechter, Francesca M Bosisio.
      While immune checkpoint-based immunotherapy (ICI) shows promising clinical results in cancer patients, only a subset of patients responds favorably. Response to ICI is dictated by complex networks of cellular interactions between malignant and non-malignant cells. Although insights into the mechanisms that modulate the pivotal anti-tumoral activity of cytotoxic T-cells (Tcy) have recently been gained, much of what has been learned is based on single-cell analyses of dissociated tumor samples, resulting in a lack of critical information about the spatial distribution of relevant cell types. Here, we used multiplexed immunohistochemistry to spatially characterize the immune landscape of metastatic melanoma from responders and non-responders to ICI. Such high-dimensional pathology maps showed that Tcy gradually evolve towards an exhausted phenotype as they approach and infiltrate the tumor. Moreover, a key cellular interaction network functionally linked Tcy and PD-L1+ macrophages. Mapping the respective spatial distributions of these two cell populations predicted response to anti-PD-1 immunotherapy with high confidence. These results suggest that baseline measurements of the spatial context should be integrated in the design of predictive biomarkers to identify patients likely to benefit from ICI.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0363
  12. Nat Rev Clin Oncol. 2022 Jul 12.
    The oligometastatic spectrum in the era of improved detection and modern systemic therapy.
    Rohan R Katipally, Sean P Pitroda, Aditya Juloori, Steven J Chmura, Ralph R Weichselbaum.
      Metastases remain the leading cause of cancer-related mortality. The oligometastasis hypothesis postulates that a spectrum of metastatic spread exists and that some patients with a limited burden of metastases can be cured with ablative therapy. Over the past decade, substantial advances in systemic therapies have resulted in considerable improvements in the outcomes of patients with metastatic cancers, warranting re-examination of the oligometastatic paradigm and the role of local ablative therapies within the context of the improved therapeutic responses, shifting patterns of disease recurrence and possible synergy with systemic treatments. Herein, we reframe the oligometastatic phenotype as a dynamic state for which locally ablative, metastasis-directed therapy improves clinical outcomes, including by prolonging survival and increasing cure rates. Important risk factors defining the metastatic spectrum are highlighted that inform both staging and therapy. Finally, we synthesize the literature on combining local therapies with modern systemic treatments, identifying general themes to optimally integrate ablative therapies in this context.
    DOI:  https://doi.org/10.1038/s41571-022-00655-9
  13. J Clin Invest. 2022 Jul 12. pii: e149551. [Epub ahead of print]
    Hematopoietic transcription factor GFI1 promotes anchorage independence by sustaining ERK activity in cancer cells.
    Hao Wang, Zhenzhen Lin, Zhe Nian, Wei Zhang, Wenxu Liu, Fei Yan, Zengtuan Xiao, Xia Wang, Zhenfa Zhang, Zhenyi Ma, Zhe Liu.
      The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. Here in this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of anchorage-independence in lung cancer cells. GFI1 elevated the numbers of circulating and lung infiltrating tumor cells in xenograft models and predicted poor prognosis of lung cancer patients. Mechanistically, GFI1 inhibited the expression of multiple adhesion molecules and facilitated substrate detachment. Concomitantly, GFI1 reconfigured chromatin structure of the RASGRP2 gene and increased its expression, causing Rap1 activation and subsequent sustained ERK activation upon detachment, and this leaded to ERK signaling dependency in tumor cells. Our studies unveiled a mechanism by which carcinoma cells hijacked a hematopoietic factor to gain anchorage independence and suggested that the intervention of ERK signaling may suppress metastasis and improve the therapeutic outcome of GFI1-positive lung cancer patients.
    Keywords:  Apoptosis survival pathways; Cancer; Cell Biology; Cell migration/adhesion; Oncology
    DOI:  https://doi.org/10.1172/JCI149551
  14. Mol Cancer. 2022 Jul 15. 21(1): 145
    CircBCAR3 accelerates esophageal cancer tumorigenesis and metastasis via sponging miR-27a-3p.
    Yong Xi, Yaxing Shen, Donglei Wu, Jingtao Zhang, Chengbin Lin, Lijie Wang, Chaoqun Yu, Bentong Yu, Weiyu Shen.
      RATIONALE: Circular RNAs (circRNAs) have been demonstrated to contribute to esophageal cancer progression. CircBCAR3 (hsa_circ_0007624) is predicted to be differentially expressed in esophageal cancer by bioinformatics analysis. We investigated the oncogenic roles and biogenesis of circBCAR3 in esophageal carcinogenesis.METHODS: Functions of circBCAR3 on cancer cell proliferation, migration, invasion, and ferroptosis were explored using the loss-of-function assays. A xenograft mouse model was used to reveal effects of circBCAR3 on xenograft growth and lung metastasis. The upstream and downstream mechanisms of circBCAR3 were investigated by bioinformatics analysis and confirmed by RNA immunoprecipitation and luciferase reporter assays. The dysregulated genes in hypoxia-induced esophageal cancer cells were identified using RNA-seq.
    RESULTS: CircBCAR3 was highly expressed in esophageal cancer tissues and cells and its expression was increased by hypoxia in vitro. Silencing of circBCAR3 repressed the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells in vitro, as well as inhibited the growth and metastasis of esophageal xenograft in mice in vivo. The hypoxia-induced promotive effects on esophageal cancer cell migration and ferroptosis were rescued by circBCAR3 knockdown. Mechanistically, circBCAR3 can interact with miR-27a-3p by the competitive endogenous RNA mechanism to upregulate transportin-1 (TNPO1). Furthermore, our investigation indicated that splicing factor quaking (QKI) is a positive regulator of circBCAR3 via targeting the introns flanking the hsa_circ_0007624-formed exons in BCAR3 pre-mRNA. Hypoxia upregulates E2F7 to transcriptionally activate QKI.
    CONCLUSION: Our research demonstrated that splicing factor QKI promotes circBCAR3 biogenesis, which accelerates esophageal cancer tumorigenesis via binding with miR-27a-3p to upregulate TNPO1. These data suggested circBCAR3 as a potential target in the treatment of esophageal cancer. Hypoxia induces the upregulation of E2F7, which transcriptionally activates QKI in esophageal cancer cells. QKI increases the formation of circBCAR3 by juxtaposing the circularized exons. CircBCAR3 binds with miR-27a-3p to promote TNPO1 expression. CircBCAR3 promoted the proliferation, migration, invasion, and ferroptosis of esophageal cancer cells by miR-27a-3p.
    Keywords:  Esophageal cancer; Ferroptosis; Hypoxia; Splicing factor quaking; hsa_circ_0007624
    DOI:  https://doi.org/10.1186/s12943-022-01615-8
  15. Nat Cancer. 2022 Jul 11.
    Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1.
    Nathaniel W Mabe, Min Huang, Guillermo N Dalton, Gabriela Alexe, Daniel A Schaefer, Anna C Geraghty, Amanda L Robichaud, Amy S Conway, Delan Khalid, Marius M Mader, Julia A Belk, Kenneth N Ross, Michal Sheffer, Miles H Linde, Nghi Ly, Winnie Yao, Maria Caterina Rotiroti, Benjamin A H Smith, Marius Wernig, Carolyn R Bertozzi, Michelle Monje, Constantine S Mitsiades, Ravindra Majeti, Ansuman T Satpathy, Kimberly Stegmaier, Robbie G Majzner.
      Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.
    DOI:  https://doi.org/10.1038/s43018-022-00405-x
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