bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022–02–06
thirty-two papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy.
  2. Astrocytic laminin-211 drives disseminated breast tumor cell dormancy in brain.
  3. Method to Isolate Dormant Cancer Cells from Heterogeneous Populations.
  4. Two Driver Mutations Exist in Osimertinib-Resistant Patient Tumors.
  5. Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer.
  6. Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.
  7. Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells.
  8. Huge cancer database yields genetic clues to metastasis.
  9. Keeping brain metastases dormant.
  10. NRF2: KEAPing Tumors Protected.
  11. Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells.
  12. Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis.
  13. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities.
  14. Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.
  15. CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression.
  16. Breaking up MTDH-SND1 to break down metastasis.
  17. Inflammatory fibroblasts make rectal cancer resistant to radiation therapy.
  18. Disruption of prostaglandin E2 signaling in cancer-associated fibroblasts limits mammary carcinoma growth but promotes metastasis.
  19. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification.
  20. Tackling metastasis.
  21. Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1.
  22. SETD2 loss perturbs the kidney cancer epigenetic landscape to promote metastasis and engenders actionable dependencies on histone chaperone complexes.
  23. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients.
  24. Functional visualization of NK Cell-mediated killing of metastatic single tumor cells.
  25. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer.
  26. Metastasis and organotropism: A look through the lens of large-scale clinical sequencing data.
  27. Remodelling of the tumour microenvironment by the kallikrein-related peptidases.
  28. Tumor-specific inter-endothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness.
  29. BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer.
  30. iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca2+ homeostasis and control tumor growth and drug resistance.
  31. Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers.
  32. Nivolumab plus ipilimumab in melanoma brain metastases.
  1. Nat Cancer. 2022 Jan;3(1): 90-107
    A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy.
    Julie S Di Martino, Ana Rita Nobre, Chandrani Mondal, Isra Taha, Eduardo F Farias, Elana J Fertig, Alexandra Naba, Julio A Aguirre-Ghiso, Jose Javier Bravo-Cordero.
      Cancer cells disseminate and seed in distant organs, where they can remain dormant for many years before forming clinically detectable metastases. Here we studied how disseminated tumor cells sense and remodel the extracellular matrix (ECM) to sustain dormancy. ECM proteomics revealed that dormant cancer cells assemble a type III collagen-enriched ECM niche. Tumor-derived type III collagen is required to sustain tumor dormancy, as its disruption restores tumor cell proliferation through DDR1-mediated STAT1 signaling. Second-harmonic generation two-photon microscopy further revealed that the dormancy-to-reactivation transition is accompanied by changes in type III collagen architecture and abundance. Analysis of clinical samples revealed that type III collagen levels were increased in tumors from patients with lymph node-negative head and neck squamous cell carcinoma compared to patients who were positive for lymph node colonization. Our data support the idea that the manipulation of these mechanisms could serve as a barrier to metastasis through disseminated tumor cell dormancy induction.
    DOI:  https://doi.org/10.1038/s43018-021-00291-9
  2. Nat Cancer. 2022 Jan;3(1): 25-42
    Astrocytic laminin-211 drives disseminated breast tumor cell dormancy in brain.
    Jinxiang Dai, Patrick J Cimino, Kenneth H Gouin, Candice A Grzelak, Alexander Barrett, Andrea R Lim, Annalyssa Long, Stephanie Weaver, Lindsey T Saldin, Aiyedun Uzamere, Vera Schulte, Nigel Clegg, Laura Pisarsky, David Lyden, Mina J Bissell, Simon Knott, Alana L Welm, Jason H Bielas, Kirk C Hansen, Frank Winkler, Eric C Holland, Cyrus M Ghajar.
      Although dormancy is thought to play a key role in the metastasis of breast tumor cells to the brain, our knowledge of the molecular mechanisms regulating disseminated tumor cell (DTC) dormancy in this organ is limited. Here using serial intravital imaging of dormant and metastatic triple-negative breast cancer lines, we identify escape from the single-cell or micrometastatic state as the rate-limiting step towards brain metastasis. We show that every DTC occupies a vascular niche, with quiescent DTCs residing on astrocyte endfeet. At these sites, astrocyte-deposited laminin-211 drives DTC quiescence by inducing the dystroglycan receptor to associate with yes-associated protein, thereby sequestering it from the nucleus and preventing its prometastatic functions. These findings identify a brain-specific mechanism of DTC dormancy and highlight the need for a more thorough understanding of tumor dormancy to develop therapeutic approaches that prevent brain metastasis.
    DOI:  https://doi.org/10.1038/s43018-021-00297-3
  3. Methods Mol Biol. 2022 ;2394 19-29
    Method to Isolate Dormant Cancer Cells from Heterogeneous Populations.
    Julian A Preciado, Alptekin Aksan.
      Cancer recurrence is responsible for a high percentage of cancer-related deaths. Primary tumor removal, chemotherapy, and radiotherapy often leave behind cancer cells that are clinically undetectable. Recent evidence has shown that subpopulations of these residual cancer cells enter into a prolonged dormant state, remaining quiescent for months to years, and eventually lead to metastases and relapse (Sosa et al. Nat Rev Cancer 14:611-622, 2014). Identifying the presence of and isolating these dormancy-capable cells (DCCs) from resected tumors or bodily fluids may therefore provide an opportunity to understand their biology and develop personalized treatments for patients at risk for relapse. Physical confinement in a stiff and porous 3D matrix, which inhibits proliferation, migration, and growth of the immobilized cells, has been shown to isolate DCC populations (Preciado et al. Technology 05:1-10, 2017; Reátegui et al. J Mater Chem B 2:7440-7448, 2014). Isolated DCCs can then be recovered from the gel and analyzed. Here we describe this immobilization method that can be used to isolate DCCs from heterogeneous cell populations that may also include dormancy-incapable cancer cells and host cells.
    Keywords:  Cancer relapse; Cell immobilization; Dormant cell isolation; Physical confinement; Silica encapsulation; Single cell cancer dormancy
    DOI:  https://doi.org/10.1007/978-1-0716-1811-0_2
  4. Cancer Discov. 2022 Feb 04.
    Two Driver Mutations Exist in Osimertinib-Resistant Patient Tumors.
      Single cells demonstrate additional driver alterations along with initial EGFR mutations to drive resistance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-019
  5. Nat Cancer. 2022 Jan;3(1): 60-74
    Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer.
    Minhong Shen, Heath A Smith, Yong Wei, Yi-Zhou Jiang, Sheng Zhao, Nicole Wang, Michelle Rowicki, Yong Tang, Xiang Hang, Songyang Wu, Liling Wan, Zhi-Ming Shao, Yibin Kang.
      Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.
    DOI:  https://doi.org/10.1038/s43018-021-00280-y
  6. Nat Cancer. 2022 Jan;3(1): 43-59
    Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.
    Minhong Shen, Yong Wei, Hahn Kim, Liling Wan, Yi-Zhou Jiang, Xiang Hang, Michael Raba, Stacy Remiszewski, Michelle Rowicki, Cheng-Guo Wu, Songyang Wu, Lanjing Zhang, Xin Lu, Min Yuan, Heath A Smith, Aiping Zheng, Joseph Bertino, John F Jin, Yongna Xing, Zhi-Ming Shao, Yibin Kang.
      Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.
    DOI:  https://doi.org/10.1038/s43018-021-00279-5
  7. Nat Commun. 2022 Feb 02. 13(1): 626
    Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells.
    Lucia Borriello, Anouchka Coste, Brian Traub, Ved P Sharma, George S Karagiannis, Yu Lin, Yarong Wang, Xianjun Ye, Camille L Duran, Xiaoming Chen, Madeline Friedman, Maria Soledad Sosa, Dan Sun, Erica Dalla, Deepak K Singh, Maja H Oktay, Julio A Aguirre-Ghiso, John S Condeelis, David Entenberg.
      Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy.
    DOI:  https://doi.org/10.1038/s41467-022-28076-3
  8. Nature. 2022 Feb 03.
    Huge cancer database yields genetic clues to metastasis.
      
    Keywords:  Cancer
    DOI:  https://doi.org/10.1038/d41586-022-00236-x
  9. Nat Cancer. 2022 Jan;3(1): 3-5
    Keeping brain metastases dormant.
    Imran Khan, Patricia S Steeg.
      
    DOI:  https://doi.org/10.1038/s43018-021-00321-6
  10. Cancer Discov. 2022 Jan 31.
    NRF2: KEAPing Tumors Protected.
    Ray Pillai, Makiko Hayashi, Anastasia-Maria Zavitsanou, Thales Papagiannakopoulos.
      The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance. SIGNIFICANCE: Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0922
  11. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2120617119. [Epub ahead of print]119(6):
    Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells.
    Arin B Aurora, Vishal Khivansara, Ashley Leach, Jennifer G Gill, Misty Martin-Sandoval, Chendong Yang, Stacy Y Kasitinon, Divya Bezwada, Alpaslan Tasdogan, Wen Gu, Thomas P Mathews, Zhiyu Zhao, Ralph J DeBerardinis, Sean J Morrison.
      The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there is limited insight into its role in metastasis, when some cancer cells experience high levels of oxidative stress. To address this, we mutated the substrate binding site of glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, in patient-derived melanomas. G6PD mutant melanomas had significantly decreased G6PD enzymatic activity and depletion of intermediates in the oxidative pentose phosphate pathway. Reduced G6PD function had little effect on the formation of primary subcutaneous tumors, but when these tumors spontaneously metastasized, the frequency of circulating melanoma cells in the blood and metastatic disease burden were significantly reduced. G6PD mutant melanomas exhibited increased levels of reactive oxygen species, decreased NADPH levels, and depleted glutathione as compared to control melanomas. G6PD mutant melanomas compensated for this increase in oxidative stress by increasing malic enzyme activity and glutamine consumption. This generated a new metabolic vulnerability as G6PD mutant melanomas were more dependent upon glutaminase than control melanomas, both for oxidative stress management and anaplerosis. The oxidative pentose phosphate pathway, malic enzyme, and glutaminolysis thus confer layered protection against oxidative stress during metastasis.
    Keywords:  glutaminolysis; melanoma; metastasis; oxidative stress; pentose phosphate pathway
    DOI:  https://doi.org/10.1073/pnas.2120617119
  12. Nat Commun. 2022 Feb 03. 13(1): 669
    Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis.
    Yiwu Yan, Bo Zhou, Chen Qian, Alex Vasquez, Mohini Kamra, Avradip Chatterjee, Yeon-Joo Lee, Xiaopu Yuan, Leigh Ellis, Dolores Di Vizio, Edwin M Posadas, Natasha Kyprianou, Beatrice S Knudsen, Kavita Shah, Ramachandran Murali, Arkadiusz Gertych, Sungyong You, Michael R Freeman, Wei Yang.
      Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.
    DOI:  https://doi.org/10.1038/s41467-022-28340-6
  13. Lancet Oncol. 2022 Feb;pii: S1470-2045(21)00596-9. [Epub ahead of print]23(2): e62-e74
    Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities.
    Diana D Shi, Jimmy A Guo, Hannah I Hoffman, Jennifer Su, Mari Mino-Kenudson, Jaimie L Barth, Jason M Schenkel, Jay S Loeffler, Helen A Shih, Theodore S Hong, Jennifer Y Wo, Andrew J Aguirre, Tyler Jacks, Lei Zheng, Patrick Y Wen, Timothy C Wang, William L Hwang.
      With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience.
    DOI:  https://doi.org/10.1016/S1470-2045(21)00596-9
  14. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2107599119. [Epub ahead of print]119(6):
    Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.
    Qin Xu, Chao Wang, Jia-Xin Zhou, Zhi-Mei Xu, Juan Gao, Pengfei Sui, Colum P Walsh, Hongbin Ji, Guo-Liang Xu.
      Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of KrasG12D -driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, the premalignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of β-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targeting Wnt signaling.
    Keywords:  DNA dioxygenases; Wnt antagonizing genes; epigenetic barriers; lung adenocarcinoma; mouse models
    DOI:  https://doi.org/10.1073/pnas.2107599119
  15. Sci Transl Med. 2022 Feb 02. 14(630): eabf5473
    CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression.
    Meiling Zhang, Zongzhi Z Liu, Keisuke Aoshima, Wesley L Cai, Hongyin Sun, Tianrui Xu, Yangyi Zhang, Yongyan An, Jocelyn F Chen, Lok Hei Chan, Asako Aoshima, Sabine M Lang, Zhenwei Tang, Xuanlin Che, Yao Li, Sara J Rutter, Veerle Bossuyt, Xiang Chen, Jon S Morrow, Lajos Pusztai, David L Rimm, Mingzhu Yin, Qin Yan.
      Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as TNC, MMP2, and VEGFA, and cytokine genes CSF1 and CXCL1, which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB-mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer.
    DOI:  https://doi.org/10.1126/scitranslmed.abf5473
  16. Nat Cancer. 2022 Jan;3(1): 6-8
    Breaking up MTDH-SND1 to break down metastasis.
    Qingwen Jiang, Karuna Ganesh.
      
    DOI:  https://doi.org/10.1038/s43018-021-00320-7
  17. Cancer Cell. 2022 Jan 19. pii: S1535-6108(22)00007-1. [Epub ahead of print]
    Inflammatory fibroblasts make rectal cancer resistant to radiation therapy.
    Rana Mhaidly, Fatima Mechta-Grigoriou.
      Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Still, the molecular mechanisms that drive CRC therapy resistance are incompletely understood. In this issue of Cancer Cell, Nicolas et al. combine several approaches to unravel a critical role for inflammatory cancer-associated fibroblasts (iCAFs) and interleukin 1α (IL1α) signaling in radiotherapy resistance.
    DOI:  https://doi.org/10.1016/j.ccell.2022.01.005
  18. Cancer Res. 2022 Feb 01. pii: canres.2116.2021. [Epub ahead of print]
    Disruption of prostaglandin E2 signaling in cancer-associated fibroblasts limits mammary carcinoma growth but promotes metastasis.
    Eiman Elwakeel, Mirko Brüggemann, Jessica Wagih, Olga Lityagina, Mohammed A F Elewa, Yingying Han, Timo Froemel, Rüdiger Popp, Adele M Nicolas, Yannick Schreiber, Elise Gradhand, Dominique Thomas, Rolf Nüsing, Julia Steinmetz-Späh, Rajkumar Savai, Emmanouil Fokas, Ingrid Fleming, Florian R Greten, Kathi Zarnack, Bernhard Brüne, Andreas Weigert.
      The activation and differentiation of cancer-associated fibroblasts (CAF) are involved in tumor progression. Here we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE2) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE2 signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation. CAF proliferation upon EP3 inhibition required p38 MAPK signaling. Mechanistically, TGF-β-activated kinase-like protein (TAK1L), which was identified as a negative regulator of p38 MAPK activation, was decreased following ablation of mPGES-1 or EP3. In contrast to its effects on primary tumor growth, disruption of PGE2 signaling in CAFs induced epithelial to mesenchymal transition in cancer organoids and promoted metastasis in mice. Moreover, TAK1L expression in CAFs was associated with decreased CAF activation, reduced metastasis, and prolonged survival in human breast cancer. These data characterize a new pathway of regulating inflammatory CAF activation, which affects breast cancer progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2116
  19. Mol Cancer. 2022 Feb 03. 21(1): 34
    Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification.
    Yiyang Hu, Chunli Gong, Zhibin Li, Jiao Liu, Yang Chen, Yu Huang, Qiang Luo, Sumin Wang, Yu Hou, Shiming Yang, Yufeng Xiao.
       BACKGROUND: Gastric cancer (GC) is one of the most pernicious tumors that seriously harm human healthcare. GC metastasis is one of the prime cause of failed cancer treatment, but correlation between N6-methyladenosine (m6A) and GC metastasis was less reported.
    METHODS: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of GC tissues was conducted. Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry (IHC) were taken to determine the expression of ALKBH5 in GC tissues and cell lines. RNA-seq together with MeRIP-qRT-PCR was used to screen the target gene of ALKBH5. RNA pulldown, mass spectrometry and RNA immunoprecipitation (RIP) were used to search the "reader" protein of target gene. The mechanism was also validated via a tail vein injection method for lung metastasis model.
    RESULTS: Decreased expression of ALKBH5 was detected in GC samples, and it was correlated with clinical tumor distal metastasis and lymph node metastasis. ALKBH5 interference promoted metastasis of GC cells and this effect was closely related to the demethylase activity of ALKBH5. PKMYT1, as a downstream target of ALKBH5, promoted invasion and migration in GC. Caused by ALKBH5 knockdown or its demethylase activity mutation, upregulated expression of PKMYT1 indicated that ALKBH5 modulates expression of PKMYT1 in an m6A-dependent manner. IGF2BP3 helped stabilize the mRNA stability of PKMYT1 via its m6A modification site.
    CONCLUSIONS: This study established an ALKBH5-PKMYT1-IGF2BP3 regulation system in metastasis, representing a new therapeutic target for GC metastasis.
    Keywords:  ALKBH5; Demethylase activity; Gastric cancer; Invasion; Metastasis; PKMYT1
    DOI:  https://doi.org/10.1186/s12943-022-01522-y
  20. Nat Cancer. 2022 Jan;3(1): 1-2
    Tackling metastasis.
      
    DOI:  https://doi.org/10.1038/s43018-021-00327-0
  21. Oncogene. 2022 Jan 29.
    Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1.
    Han-Seok Jeong, Da-Hye Lee, Seung-Hoon Kim, Chang-Han Lee, Hyun Mu Shin, Hang-Rae Kim, Chung-Hyun Cho.
      Diabetes mellitus (DM) characterized by hyperglycemia is a chronic metabolic disorder that leads to many symptoms and vascular complications. Despite the close association between DM and cancer progression, the response and role of endothelial cells (ECs) under diabetic conditions in tumor metastasis remain to be elucidated. In this study, we sought to determine whether and how ECs under diabetic conditions contribute to tumor metastasis. We have taken advantage of syngeneic mouse tumor models of Lewis lung carcinoma (LLC) and melanoma (B16F10) cells and a streptozotocin (STZ)-induced hyperglycemia model. We demonstrated that hyperglycemia increased the metastasis of LLC and B16F10 cells in an experimental metastasis model with an intravenous injection of the tumor cells. We also found that hyperglycemia promoted lung metastasis of tumor cells by increasing the adhesiveness of ECs to facilitate the adhesion of tumor cells to ECs rather than affecting the metastatic behavior of tumor cells themselves. From the analysis of gene expression in primary lung ECs from STZ-treated mice, we identified that vWF promoted the adhesion of tumor cells to ECs and the transendothelial migration of tumor cells. Mechanistically, hyperglycemia-induced oxidative stress in ECs, and increased oxidative stress enhanced vWF expression in ECs through an increase in the transcription factor GATA1. These results provide evidence for the role of vWF in ECs in promoting hyperglycemia-induced tumor metastasis and potential therapeutic targets for the regulation of vWF expression in ECs and hyperglycemia-induced tumor metastasis.
    DOI:  https://doi.org/10.1038/s41388-022-02207-y
  22. Nat Cancer. 2022 Feb 03.
    SETD2 loss perturbs the kidney cancer epigenetic landscape to promote metastasis and engenders actionable dependencies on histone chaperone complexes.
    Yuchen Xie, Merve Sahin, Sonali Sinha, Yufeng Wang, Amrita M Nargund, Yang Lyu, Song Han, Yiyu Dong, James J Hsieh, Christina S Leslie, Emily H Cheng.
      SETD2 is a histone H3 lysine 36 (H3K36) trimethyltransferase that is mutated with high prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2 loss promotes metastasis remains unclear. In this study, we used a SETD2-mutant (SETD2MT) metastatic ccRCC human-derived cell line and xenograft models and showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice in a matrix metalloproteinase 1 (MMP1)-dependent manner. An integrated multiomics analysis using assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) established a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcriptional output through regulation of chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through the targeting of specific histone chaperone complexes, including ASF1A/ASF1B and SPT16. Overall, SETD2 loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s43018-021-00316-3
  23. Cell. 2022 Feb 03. pii: S0092-8674(22)00003-4. [Epub ahead of print]185(3): 563-575.e11
    Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients.
    Bastien Nguyen, Christopher Fong, Anisha Luthra, Shaleigh A Smith, Renzo G DiNatale, Subhiksha Nandakumar, Henry Walch, Walid K Chatila, Ramyasree Madupuri, Ritika Kundra, Craig M Bielski, Brooke Mastrogiacomo, Mark T A Donoghue, Adrienne Boire, Sarat Chandarlapaty, Karuna Ganesh, James J Harding, Christine A Iacobuzio-Donahue, Pedram Razavi, Ed Reznik, Charles M Rudin, Dmitriy Zamarin, Wassim Abida, Ghassan K Abou-Alfa, Carol Aghajanian, Andrea Cercek, Ping Chi, Darren Feldman, Alan L Ho, Gopakumar Iyer, Yelena Y Janjigian, Michael Morris, Robert J Motzer, Eileen M O'Reilly, Michael A Postow, Nitya P Raj, Gregory J Riely, Mark E Robson, Jonathan E Rosenberg, Anton Safonov, Alexander N Shoushtari, William Tap, Min Yuen Teo, Anna M Varghese, Martin Voss, Rona Yaeger, Marjorie G Zauderer, Nadeem Abu-Rustum, Julio Garcia-Aguilar, Bernard Bochner, Abraham Hakimi, William R Jarnagin, David R Jones, Daniela Molena, Luc Morris, Eric Rios-Doria, Paul Russo, Samuel Singer, Vivian E Strong, Debyani Chakravarty, Lora H Ellenson, Anuradha Gopalan, Jorge S Reis-Filho, Britta Weigelt, Marc Ladanyi, Mithat Gonen, Sohrab P Shah, Joan Massague, Jianjiong Gao, Ahmet Zehir, Michael F Berger, David B Solit, Samuel F Bakhoum, Francisco Sanchez-Vega, Nikolaus Schultz.
      Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.
    Keywords:  DNA sequencing; cancer; clinical sequencing; genomics; metastasis; molecular profiling; mutations; next-generation sequencing; organotropism; pan-cancer
    DOI:  https://doi.org/10.1016/j.cell.2022.01.003
  24. Elife. 2022 Feb 03. pii: e76269. [Epub ahead of print]11
    Functional visualization of NK Cell-mediated killing of metastatic single tumor cells.
    Hiroshi Ichise, Shoko Tsukamoto, Tsuyoshi Hirashima, Yoshinobu Konishi, Choji Oki, Shinya Tsukiji, Satoshi Iwano, Atsushi Miyawaki, Kenta Sumiyama, Kenta Terai, Michiyuki Matsuda.
      Natural killer (NK) cells lyse invading tumor cells to limit metastatic growth in the lung, but how some cancers evade this host protective mechanism to establish a growing lesion is unknown. Here we have combined ultra-sensitive bioluminescence imaging with intravital two-photon microscopy involving genetically-encoded biosensors to examine this question. NK cells eliminated disseminated tumor cells from the lung within 24 hrs of arrival, but not thereafter. Intravital dynamic imaging revealed that 50% of NK-tumor cell encounters lead to tumor cell death in the first 4 hrs after tumor cell arrival, but after 24 hrs of arrival, nearly 100% of the interactions result in the survival of the tumor cell. During this 24 hrs period, the probability of ERK activation in NK cells upon encountering the tumor cells was decreased from 68% to 8%, which correlated with the loss of the activating ligand CD155/PVR/Necl5 from the tumor cell surface. Thus, by quantitatively visualizing the NK-tumor cell interaction at the early stage of metastasis, we have revealed the crucial parameters of NK cell immune surveillance in the lung.
    Keywords:  cell biology; immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.76269
  25. Cancer Cell. 2022 Jan 29. pii: S1535-6108(22)00006-X. [Epub ahead of print]
    Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer.
    Adele M Nicolas, Marina Pesic, Esther Engel, Paul K Ziegler, Markus Diefenhardt, Kilian B Kennel, Florian Buettner, Claire Conche, Valentina Petrocelli, Eiman Elwakeel, Andreas Weigert, Anna Zinoveva, Maximilian Fleischmann, Björn Häupl, Cem Karakütük, Hanibal Bohnenberger, Mohammed H Mosa, Lars Kaderali, Jochen Gaedcke, Michael Ghadimi, Franz Rödel, Melek C Arkan, Thomas Oellerich, Claus Rödel, Emmanouil Fokas, Florian R Greten.
      Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. In rectal cancer patients we find that inflammatory cancer-associated fibroblasts (iCAFs) are associated with poor chemoradiotherapy response. Employing a murine rectal cancer model or patient-derived tumor organoids and primary stroma cells, we show that, upon irradiation, interleukin-1α (IL-1α) not only polarizes cancer-associated fibroblasts toward the inflammatory phenotype but also triggers oxidative DNA damage, thereby predisposing iCAFs to p53-mediated therapy-induced senescence, which in turn results in chemoradiotherapy resistance and disease progression. Consistently, IL-1 inhibition, prevention of iCAFs senescence, or senolytic therapy sensitizes mice to irradiation, while lower IL-1 receptor antagonist serum levels in rectal patients correlate with poor prognosis. Collectively, we unravel a critical role for iCAFs in rectal cancer therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of cancer-associated fibroblasts senescence.
    Keywords:  IL-1 signalling; IL1RN SNP; cancer-associated fibroblasts; neoadjuvant therapy; rectal cancer; senescence
    DOI:  https://doi.org/10.1016/j.ccell.2022.01.004
  26. Cancer Cell. 2022 Jan 28. pii: S1535-6108(22)00013-7. [Epub ahead of print]
    Metastasis and organotropism: A look through the lens of large-scale clinical sequencing data.
    Alexander Coulton, Samra Turajlic.
      In Cell, Nguyen et al. utilize targeted panel sequencing combined with electronic health record data to study metastasis and organotropism in a large cohort of 25,775 patients. Their genomic and clinical data have been made freely available as a resource for use by the community.
    DOI:  https://doi.org/10.1016/j.ccell.2022.01.011
  27. Nat Rev Cancer. 2022 Jan 31.
    Remodelling of the tumour microenvironment by the kallikrein-related peptidases.
    Srilakshmi Srinivasan, Thomas Kryza, Jyotsna Batra, Judith Clements.
      Kallikrein-related peptidases (KLKs) are critical regulators of the tumour microenvironment. KLKs are proteolytic enzymes regulating multiple functions of bioactive molecules including hormones and growth factors, membrane receptors and the extracellular matrix architecture involved in cancer progression and metastasis. Perturbations of the proteolytic cascade generated by these peptidases, and their downstream signalling actions, underlie tumour emergence or blockade of tumour growth. Recent studies have also revealed their role in tumour immune suppression and resistance to cancer therapy. Here, we present an overview of the complex biology of the KLK family and its context-dependent nature in cancer, and discuss the different therapeutic strategies available to potentially target these proteases.
    DOI:  https://doi.org/10.1038/s41568-021-00436-z
  28. J Clin Invest. 2022 Feb 01. pii: e153626. [Epub ahead of print]
    Tumor-specific inter-endothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness.
    Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota.
      Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans, and that its expression correlates negatively with long-term survival. Endothelial-specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed "oxygen-glucose uncoupling", which suppresses tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the anti-tumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms non-canonical inter-endothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrate the existence of tumor-specific inter-endothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.
    Keywords:  Angiogenesis; Cancer; Endothelial cells; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI153626
  29. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2109133119. [Epub ahead of print]119(6):
    BRD4-directed super-enhancer organization of transcription repression programs links to chemotherapeutic efficacy in breast cancer.
    Beibei Liu, Xinhua Liu, Lulu Han, Xing Chen, Xiaodi Wu, Jiajing Wu, Dong Yan, Yue Wang, Shumeng Liu, Lin Shan, Yu Zhang, Yongfeng Shang.
      BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.
    Keywords:  BRD4; JQ1 resistance; LSD1/NuRD complex; super-enhancer
    DOI:  https://doi.org/10.1073/pnas.2109133119
  30. Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2111380119. [Epub ahead of print]119(6):
    iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca2+ homeostasis and control tumor growth and drug resistance.
    Shanliang Zheng, Dong Zhao, Guixue Hou, Song Zhao, Wenxin Zhang, Xingwen Wang, Li Li, Liang Lin, Tie-Shan Tang, Ying Hu.
      Ca2+ release from the endoplasmic reticulum (ER) is an essential event in the modulation of Ca2+ homeostasis, which is coordinated by multiple biological processes, ranging from cell proliferation to apoptosis. Deregulated Ca2+ homeostasis is linked with various cancer hallmarks; thus, uncovering the mechanisms underlying Ca2+ homeostasis dynamics may lead to new anticancer treatment strategies. Here, we demonstrate that a reported Ca2+-channel protein TMCO1 (transmembrane and coiled-coil domains 1) is overexpressed in colon cancer tissues at protein levels but not at messenger RNA levels in colon cancer. Further study revealed that TMCO1 is a substrate of ER-associated degradation E3 ligase Gp78. Intriguingly, Gp78-mediated TMCO1 degradation at K186 is under the control of the iASPP (inhibitor of apoptosis-stimulating protein of p53) oncogene. Mechanistically, iASPP robustly reduces ER Ca2+ stores, mainly by competitively binding with Gp78 and interfering with Gp78-mediated TMCO1 degradation. A positive correlation between iASPP and TMCO1 proteins is further validated in human colon tissues. Inhibition of iASPP-TMCO1 axis promotes cytosolic Ca2+ overload-induced apoptotic cell death, reducing tumor growth both in vitro and in vivo. Thus, iASPP-TMCO1 represents a promising anticancer treatment target by modulating Ca2+ homeostasis.
    Keywords:  TMCO1; apoptosis; calcium; endoplasmic reticulum; iASPP
    DOI:  https://doi.org/10.1073/pnas.2111380119
  31. Science. 2022 Feb 03. eabl5447
    Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers.
    Frank J Lowery, Sri Krishna, Rami Yossef, Neilesh B Parikh, Praveen D Chatani, Nikolaos Zacharakis, Maria R Parkhurst, Noam Levin, Sivasish Sindiri, Abraham Sachs, Kyle J Hitscherich, Zhiya Yu, Nolan R Vale, Yong-Chen Lu, Zhili Zheng, Li Jia, Jared J Gartner, Victoria K Hill, Amy R Copeland, Shirley K Nah, Robert V Masi, Billel Gasmi, Scott Kivitz, Biman C Paria, Maria Florentin, Sanghyun P Kim, Ken-Ichi Hanada, Yong F Li, Lien T Ngo, Satyajit Ray, Mackenzie L Shindorf, Shoshana T Levi, Ryan Shepherd, Chris Toy, Anup Y Parikh, Todd D Prickett, Michael C Kelly, Rachel Beyer, Stephanie L Goff, James C Yang, Paul F Robbins, Steven A Rosenberg.
      The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge to engineering cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TIL). Neoantigen-specific TIL exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TIL. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs targeting driver neoantigens and non-mutated viral/tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TIL across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.
    DOI:  https://doi.org/10.1126/science.abl5447
  32. Lancet Oncol. 2022 Feb;pii: S1470-2045(22)00010-9. [Epub ahead of print]23(2): e52
    Nivolumab plus ipilimumab in melanoma brain metastases.
    Alessandro Rizzo.
      
    DOI:  https://doi.org/10.1016/S1470-2045(22)00010-9
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:29.