bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–11–14
twenty papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. The Role of Tumor Microenvironment and Exosomes in Dormancy and Relapse.
  2. Dietary palmitic acid promotes a prometastatic memory via Schwann cells.
  3. A rare insight into the immunosuppressive landscape of prostate cancer bone metastases.
  4. Diverse alterations associated with resistance to KRAS(G12C) inhibition.
  5. Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death.
  6. Mutation in Abl kinase with altered drug-binding kinetics indicates a novel mechanism of imatinib resistance.
  7. Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses.
  8. Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy.
  9. TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change.
  10. Nanoparticle delivery of miR-122 inhibits colorectal cancer liver metastasis.
  11. Immune activation and evolution through chemotherapy plus checkpoint blockade in triple-negative breast cancer.
  12. Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer.
  13. MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.
  14. Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape.
  15. Targeting bone microenvironments for treatment and early detection of cancer bone metastatic niches.
  16. IL-6 induced cGGNBP2 encodes a novel protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma.
  17. Revisiting the HIF switch in the tumor and its immune microenvironment.
  18. Inhibition of FGFR reactivates IFNγ signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies.
  19. Decoding therapy resistance in liver tumours: a giant leap.
  20. Myeloid-cell derived oxidized lipids and regulation of the tumor microenvironment.
  1. Semin Cancer Biol. 2021 Oct 29. pii: S1044-579X(21)00232-7. [Epub ahead of print]
    The Role of Tumor Microenvironment and Exosomes in Dormancy and Relapse.
    Shireen Attaran, Mina J Bissell.
      Recent advancements in the field of cancer have established that the process of metastasis is organ-specific with tumor cell dissemination occurring in the very early stages of disease. Pre-metastatic niches are actively remodeled and transformed by both primary tumor specific factors and by influences from the extracellular matrix.Although improvements in cancer therapies have significantly improved outcomes in patients with early stage disease, the risk of recurrence and relapse leading to mortality remains high. Recent studies have emerged highlighting the influence of dormant tumor cells and exosomes as key players in cancer relapse. In this review we discuss the critical mediators of tumor progression and their link to cancer dormancy, while also exploring possible therapeutics for targeting relapse.
    Keywords:  Cancer; dormancy; extracellular matrix; microenvironment; relapse
    DOI:  https://doi.org/10.1016/j.semcancer.2021.09.008
  2. Nature. 2021 Nov 10.
    Dietary palmitic acid promotes a prometastatic memory via Schwann cells.
    Gloria Pascual, Diana Domínguez, Marc Elosúa-Bayes, Felipe Beckedorff, Carmelo Laudanna, Claudia Bigas, Delphine Douillet, Carolina Greco, Aikaterini Symeonidi, Inmaculada Hernández, Sara Ruiz Gil, Neus Prats, Coro Bescós, Ramin Shiekhattar, Moran Amit, Holger Heyn, Ali Shilatifard, Salvador Aznar Benitah.
      Fatty acid uptake and altered metabolism constitute hallmarks of metastasis1,2, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood3,4. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.
    DOI:  https://doi.org/10.1038/s41586-021-04075-0
  3. Cancer Cell. 2021 Nov 08. pii: S1535-6108(21)00493-1. [Epub ahead of print]39(11): 1450-1452
    A rare insight into the immunosuppressive landscape of prostate cancer bone metastases.
    Claudia Palena, James L Gulley.
      Therapeutic options for metastatic prostate cancer patients are currently limited. In this issue of Cancer Cell, Kfoury et al. characterized the tumor and immune compartments of prostate cancer bone metastasis, revealing a mechanism of immunosuppression that involves infiltration with M2 macrophages and T cell exhaustion mediated by the CCL20-CCR6 axis.
    DOI:  https://doi.org/10.1016/j.ccell.2021.09.004
  4. Nature. 2021 Nov 10.
    Diverse alterations associated with resistance to KRAS(G12C) inhibition.
    Yulei Zhao, Yonina R Murciano-Goroff, Jenny Y Xue, Agnes Ang, Jessica Lucas, Trang T Mai, Arnaud F Da Cruz Paula, Anne Y Saiki, Deanna Mohn, Pragathi Achanta, Ann E Sisk, Kanika S Arora, Rohan S Roy, Dongsung Kim, Chuanchuan Li, Lee P Lim, Mark Li, Amber Bahr, Brian R Loomis, Elisa de Stanchina, Jorge S Reis-Filho, Britta Weigelt, Michael Berger, Gregory Riely, Kathryn C Arbour, J Russell Lipford, Bob T Li, Piro Lito.
      Inactive state-selective KRAS(G12C) inhibitors1-8 demonstrate a 30-40% response rate and result in approximately 6-month median progression-free survival in patients with lung cancer9. The genetic basis for resistance to these first-in-class mutant GTPase inhibitors remains under investigation. Here we evaluated matched pre-treatment and post-treatment specimens from 43 patients treated with the KRAS(G12C) inhibitor sotorasib. Multiple treatment-emergent alterations were observed across 27 patients, including alterations in KRAS, NRAS, BRAF, EGFR, FGFR2, MYC and other genes. In preclinical patient-derived xenograft and cell line models, resistance to KRAS(G12C) inhibition was associated with low allele frequency hotspot mutations in KRAS(G12V or G13D), NRAS(Q61K or G13R), MRAS(Q71R) and/or BRAF(G596R), mirroring observations in patients. Single-cell sequencing in an isogenic lineage identified secondary RAS and/or BRAF mutations in the same cells as KRAS(G12C), where they bypassed inhibition without affecting target inactivation. Genetic or pharmacological targeting of ERK signalling intermediates enhanced the antiproliferative effect of G12C inhibitor treatment in models with acquired RAS or BRAF mutations. Our study thus suggests a heterogenous pattern of resistance with multiple subclonal events emerging during G12C inhibitor treatment. A subset of patients in our cohort acquired oncogenic KRAS, NRAS or BRAF mutations, and resistance in this setting may be delayed by co-targeting of ERK signalling intermediates. These findings merit broader evaluation in prospective clinical trials.
    DOI:  https://doi.org/10.1038/s41586-021-04065-2
  5. Nat Commun. 2021 Nov 12. 12(1): 6572
    Apoptotic stress-induced FGF signalling promotes non-cell autonomous resistance to cell death.
    Florian J Bock, Egor Sedov, Elle Koren, Anna L Koessinger, Catherine Cloix, Désirée Zerbst, Dimitris Athineos, Jayanthi Anand, Kirsteen J Campbell, Karen Blyth, Yaron Fuchs, Stephen W G Tait.
      Damaged or superfluous cells are typically eliminated by apoptosis. Although apoptosis is a cell-autonomous process, apoptotic cells communicate with their environment in different ways. Here we describe a mechanism whereby cells under apoptotic stress can promote survival of neighbouring cells. We find that upon apoptotic stress, cells release the growth factor FGF2, leading to MEK-ERK-dependent transcriptional upregulation of pro-survival BCL-2 proteins in a non-cell autonomous manner. This transient upregulation of pro-survival BCL-2 proteins protects neighbouring cells from apoptosis. Accordingly, we find in certain cancer types a correlation between FGF-signalling, BCL-2 expression and worse prognosis. In vivo, upregulation of MCL-1 occurs in an FGF-dependent manner during skin repair, which regulates healing dynamics. Importantly, either co-treatment with FGF-receptor inhibitors or removal of apoptotic stress restores apoptotic sensitivity to cytotoxic therapy and delays wound healing. These data reveal a pathway by which cells under apoptotic stress can increase resistance to cell death in surrounding cells. Beyond mediating cytotoxic drug resistance, this process also provides a potential link between tissue damage and repair.
    DOI:  https://doi.org/10.1038/s41467-021-26613-0
  6. Proc Natl Acad Sci U S A. 2021 Nov 16. pii: e2111451118. [Epub ahead of print]118(46):
    Mutation in Abl kinase with altered drug-binding kinetics indicates a novel mechanism of imatinib resistance.
    Agatha Lyczek, Benedict-Tilman Berger, Aziz M Rangwala, YiTing Paung, Jessica Tom, Hannah Philipose, Jiaye Guo, Steven K Albanese, Matthew B Robers, Stefan Knapp, John D Chodera, Markus A Seeliger.
      Protein kinase inhibitors are potent anticancer therapeutics. For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for chronic myeloid leukemia by 80%, but 22 to 41% of patients acquire resistance to imatinib. About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain, where more than a hundred different mutations have been identified. Some mutations are located near the imatinib-binding site and cause resistance through altered interactions with the drug. However, many resistance mutations are located far from the drug-binding site, and it remains unclear how these mutations confer resistance. Additionally, earlier studies on small sets of patient-derived imatinib resistance mutations indicated that some of these mutant proteins were in fact sensitive to imatinib in cellular and biochemical studies. Here, we surveyed the resistance of 94 patient-derived Abl kinase domain mutations annotated as disease relevant or resistance causing using an engagement assay in live cells. We found that only two-thirds of mutations weaken imatinib affinity by more than twofold compared to Abl wild type. Surprisingly, one-third of mutations in the Abl kinase domain still remain sensitive to imatinib and bind with similar or higher affinity than wild type. Intriguingly, we identified three clinical Abl mutations that bind imatinib with wild type-like affinity but dissociate from imatinib considerably faster. Given the relevance of residence time for drug efficacy, mutations that alter binding kinetics could cause resistance in the nonequilibrium environment of the body where drug export and clearance play critical roles.
    Keywords:  binding kinetics; drug binding; drug resistance; imatinib; protein kinase
    DOI:  https://doi.org/10.1073/pnas.2111451118
  7. Nat Commun. 2021 Nov 11. 12(1): 6522
    Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses.
    Humberto Contreras-Trujillo, Jiya Eerdeng, Samir Akre, Du Jiang, Jorge Contreras, Basia Gala, Mary C Vergel-Rodriguez, Yeachan Lee, Aparna Jorapur, Areen Andreasian, Lisa Harton, Charles S Bramlett, Anna Nogalska, Gang Xiao, Jae-Woong Lee, Lai N Chan, Markus Müschen, Akil A Merchant, Rong Lu.
      Cellular heterogeneity is a major cause of treatment resistance in cancer. Despite recent advances in single-cell genomic and transcriptomic sequencing, it remains difficult to relate measured molecular profiles to the cellular activities underlying cancer. Here, we present an integrated experimental system that connects single cell gene expression to heterogeneous cancer cell growth, metastasis, and treatment response. Our system integrates single cell transcriptome profiling with DNA barcode based clonal tracking in patient-derived xenograft models. We show that leukemia cells exhibiting unique gene expression respond to different chemotherapies in distinct but consistent manners across multiple mice. In addition, we uncover a form of leukemia expansion that is spatially confined to the bone marrow of single anatomical sites and driven by cells with distinct gene expression. Our integrated experimental system can interrogate the molecular and cellular basis of the intratumoral heterogeneity underlying disease progression and treatment resistance.
    DOI:  https://doi.org/10.1038/s41467-021-26771-1
  8. Nat Commun. 2021 Nov 11. 12(1): 6546
    Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy.
    Steven Ngo, Ethan P Oxley, Margherita Ghisi, Maximilian M Garwood, Mark D McKenzie, Helen L Mitchell, Peter Kanellakis, Olivia Susanto, Michael J Hickey, Andrew C Perkins, Benjamin T Kile, Ross A Dickins.
      Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome.
    DOI:  https://doi.org/10.1038/s41467-021-26849-w
  9. Cell Rep. 2021 Nov 09. pii: S2211-1247(21)01458-3. [Epub ahead of print]37(6): 109979
    TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change.
    Aishwarya Payapilly, Ryan Guilbert, Tine Descamps, Gavin White, Peter Magee, Cong Zhou, Alastair Kerr, Kathryn L Simpson, Fiona Blackhall, Caroline Dive, Angeliki Malliri.
      Small-cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analyzing expression data from SCLC tumors, patient-derived models, and established cell lines, we show that the expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduces viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion is dependent upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promotes Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding fails to suppress apoptosis triggered by TIAM1 depletion. In conclusion, TIAM1-RAC1 signaling promotes SCLC cell survival via Nur77 nuclear sequestration.
    Keywords:  BCL2; Nur77; RAC; SCLC; TIAM1; apoptosis; neuroendocrine; small cell lung cancer
    DOI:  https://doi.org/10.1016/j.celrep.2021.109979
  10. Cancer Res. 2021 Nov 09. pii: canres.2269.2021. [Epub ahead of print]
    Nanoparticle delivery of miR-122 inhibits colorectal cancer liver metastasis.
    Hossein Sendi, Mostafa Yazdimamaghani, Mengying Hu, Nikhila Sultanpuram, Jie Wang, Amber S Moody, Ellie McCabe, Jiajie Zhang, Amanda Graboski, Liantao Li, Juan D Rojas, Paul A Dayton, Leaf Huang, Andrew Z Wang.
      Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as microRNA-122 (miR-122), a liver-specific microRNA (miRNA) that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer (CRC) liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented CRC liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes in involved in metastatic and cancer inflammation pathways, including several pro-inflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to anti-tumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2269
  11. Cancer Cell. 2021 Nov 08. pii: S1535-6108(21)00601-2. [Epub ahead of print]
    Immune activation and evolution through chemotherapy plus checkpoint blockade in triple-negative breast cancer.
    Siang-Boon Koh, Leif W Ellisen.
      Immune checkpoint blockade plus chemotherapy is emerging as a standard treatment for some patients with triple-negative breast cancer (TNBC). In this issue of Cancer Cell, Zhang et al. employ extensive single-cell immune compartment analyses of pre- and post-therapy TNBC, and they reveal potential mechanisms of T cell activation and patterns of immune evolution that may inform future biomarkers of response and clinical benefit.
    DOI:  https://doi.org/10.1016/j.ccell.2021.11.001
  12. Oncogene. 2021 Nov 09.
    Aberrant promoter hypermethylation inhibits RGMA expression and contributes to tumor progression in breast cancer.
    Yan Li, Hai-Ting Liu, Xu Chen, Ya-Wen Wang, Ya-Ru Tian, Ran-Ran Ma, Lin Song, Yong-Xin Zou, Peng Gao.
      Breast cancer (BC) is the most common cancer in women worldwide, and the exploration of aberrantly expressed genes might clarify tumorigenesis and help uncover new therapeutic strategies for BC. Although RGMA was recently recognized as a tumor suppressor gene, its detailed biological function and regulation in BC remain unclear. Herein, we found that RGMA was downregulated in BC tissues compared with non-tumorous breast tissues, particularly in metastatic BC samples, and that patients with low RGMA expression manifested a poorer prognosis. Furthermore, DNMT1 and DNMT3A were found to be recruited to the RGMA promoter and induced aberrant hypermethylation, resulting in downregulation of RGMA expression in BC. In contrast, RGMA overexpression suppressed BC cell proliferation and colony-formation capabilities and increased BC cell apoptosis. Furthermore, RGMA knockdown accelerated BC cell proliferation and suppressed cellular apoptosis in vitro and in vivo. Reversal of RGMA promoter methylation with 5-Aza-CdR restored RGMA expression and blocked tumor growth. Overall, DNMT1- and DNMT3A-mediated RGMA promoter hypermethylation led to downregulation of RGMA expression, and low RGMA expression contributed to BC growth via activation of the FAK/Src/PI3K/AKT-signaling pathway. Our data thus suggested that RGMA might be a promising therapeutic target in BC.
    DOI:  https://doi.org/10.1038/s41388-021-02083-y
  13. Sci Adv. 2021 Nov 12. 7(46): eabi6439
    MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.
    Qinbo Cai, Wolong Zhou, Wei Wang, Bingning Dong, Dong Han, Tao Shen, Chad J Creighton, David D Moore, Feng Yang.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abi6439
  14. Sci Immunol. 2021 Nov 12. 6(65): eabc6424
    Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape.
    Yoshiko Takeuchi, Tokiyoshi Tanegashima, Eiichi Sato, Takuma Irie, Atsuo Sai, Kota Itahashi, Shogo Kumagai, Yasuko Tada, Yosuke Togashi, Shohei Koyama, Esra A Akbay, Takahiro Karasaki, Keisuke Kataoka, Soichiro Funaki, Yasushi Shintani, Izumi Nagatomo, Hiroshi Kida, Genichiro Ishii, Tomohiro Miyoshi, Keiju Aokage, Kazuhiro Kakimi, Seishi Ogawa, Meinoshin Okumura, Masatoshi Eto, Atsushi Kumanogoh, Masahiro Tsuboi, Hiroyoshi Nishikawa.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciimmunol.abc6424
  15. J Control Release. 2021 Nov 05. pii: S0168-3659(21)00597-6. [Epub ahead of print]
    Targeting bone microenvironments for treatment and early detection of cancer bone metastatic niches.
    Hongbin Yang, Zhenyan Yu, Shuaishuai Ji, Qiang Huo, Juanzhu Yan, Yue Gao, Yimin Niu, Ming Xu, Yang Liu.
      Bone tissues are the main metastatic sites of many cancers, and bone metastasis is an important cause of death. When bone metastasis occurs, dynamic interactions between tumor cells and bone tissues promote changes in the tumor-bone microenvironments that are conducive to tumor growth and progression, which also promote several related diseases, including pathological fracture, bone pain, and hypercalcemia. Accordingly, it has obvious clinical benefits for improving the cure rate and reducing the occurrence of related diseases through targeting bone microenvironments for the treatment and early detection of cancer bone metastasis niches. In this review, we briefly analyzed the relationship between bone microstructures and tumor metastasis, as well as microenvironmental changes in osteoblasts, osteoclasts, immune cells, and extracellular and bone matrixes caused when metastatic tumor cells colonize bones. We also discuss novel designs in nanodrugs for inhibiting tumor proliferation and migration through targeting to tumor bone metastases and abnormal bone-microenvironment components. In addition, related researches on the early detection of bone and multi-organ metastases by nanoprobes are also introduced. And we look forward to provide some useful proposals and enlightenments on nanotechnology-based drug delivery and probes for the treatment and early detection of bone metastasis.
    Keywords:  Bone microenvironments; Immunotherapy; Metastatic niche; Nanoprobes; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.jconrel.2021.11.005
  16. Hepatology. 2021 Nov 10.
    IL-6 induced cGGNBP2 encodes a novel protein to promote cell growth and metastasis in intrahepatic cholangiocarcinoma.
    Hui Li, Tian Lan, Hailing Liu, Chang Liu, Junlong Dai, Lin Xu, Yunshi Cai, Guimin Hou, Kunlin Xie, Mingheng Liao, Jiaxin Li, Jiwei Huang, Kefei Yuan, Genshu Wang, Yong Zeng, Hong Wu.
       BACKGROUND & AIMS: Interleukin (IL)-6 induced tumor progression has been well established via the induction of anti-apoptotic and proliferative genes. However, whether other mechanisms such as IL-6 regulation of circular RNAs (circRNAs) may also contribute to tumor development remains unknown.
    APPROACH & RESULTS: High-throughput RNA-seq was used to identify the differentially expressed circRNAs upon IL-6 stimulation in intrahepatic cholangiocarcinoma (ICC) cells. CircRNA GGNBP2 (derived from ggnbp2 gene, termed as cGGNBP2) was upregulated by IL-6 treatment in a time and concentration-dependent manner. The biogenesis of cGGNBP2 was regulated by RNA-binding protein DHX9, which was also mediated by IL-6 exposure. Mass spectrometry and western blotting identified a novel protein-cGGNBP2-184aa encoded by cGGNBP2. cGGNBP2-184aa promoted ICC cell proliferation and metastasis in vitro and in vivo. Mechanistically, cGGNBP2-184aa directly interacted with STAT3, phosphorylated STAT3Tyr705 , and played a positive regulatory role in modulating IL-6/STAT3 signaling. IL-6/cGGNBP2-184aa/STAT3 formed a positive feedback loop to sustain constitutive activation of IL-6/STAT3 signaling. Elevated cGGNBP2 expression was correlated with poor prognosis of ICC patients and was identified as an independent risk factor for patient prognosis.
    CONCLUSIONS: Our study demonstrates that cGGNBP2-184aa, a novel protein encoded by IL-6 induced cGGNBP2, formed a positive feedback loop to facilitate ICC progression and may serves as an auxiliary target for clinical IL-6/STAT3-targeting treatments in ICC.
    Keywords:  Circular RNA; IL-6/STAT3 signaling; Intrahepatic cholangiocarcinoma; Novel protein; feedback loop
    DOI:  https://doi.org/10.1002/hep.32232
  17. Trends Cancer. 2021 Nov 04. pii: S2405-8033(21)00209-0. [Epub ahead of print]
    Revisiting the HIF switch in the tumor and its immune microenvironment.
    Sophie J Cowman, Mei Yee Koh.
      Hypoxia is a hallmark of all solid tumors and their metastases. This leads to activation of the hypoxia-inducible factor (HIF) family of transcription factors, which modulate gene expression within both tumor cells and immune cells within the tumor microenvironment, influencing tumor progression and treatment response. The best characterized HIF isoforms, HIF-1α and HIF-2α, show nonoverlapping and often antagonistic roles. With the recent availability of inhibitors that target one or both HIFs, including the first-in-class selective HIF-2α inhibitor belzutifan, the prospect of HIF-α isoform-selective targeting is now a reality. Here, we summarize current knowledge on the unique contributions of the two HIF-α isoforms to tumor progression in the context of the complex tumor immune microenvironment, highlighting important considerations for therapy.
    Keywords:  HIF-1α; HIF-2α; cancer therapy; hypoxia; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2021.10.004
  18. Cancer Res. 2021 Nov 09. pii: canres.2426.2020. [Epub ahead of print]
    Inhibition of FGFR reactivates IFNγ signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies.
    Yusuke Adachi, Hiroshi Kamiyama, Kenji Ichikawa, Sayo Fukushima, Yoichi Ozawa, Shogo Yamaguchi, Satoshi Goda, Takayuki Kimura, Kotaro Kodama, Masahiro Matsuki, Saori Watanabe Miyano, Akira Yokoi, Yu Kato, Yasuhiro Funahashi.
      Combination therapies consisting of immune checkpoint inhibitors plus anti-vascular endothelial growth factor (VEGF) therapy show enhanced antitumor activity and are approved treatments for patients with renal cell carcinoma (RCC). The immunosuppressive roles of VEGF in the tumor microenvironment are well studied, but those of fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling remain largely unknown. Lenvatinib is a receptor tyrosine kinase inhibitor that targets both VEGF receptor (VEGFR) and FGFR. Here, we examine the antitumor activity of anti-PD-1 monoclonal antibody (mAb) combined with either lenvatinib or axitinib, a VEGFR-selective inhibitor, in RCC. Both combination treatments showed greater antitumor activity and longer survival in mouse models versus either single-agent treatment, whereas anti-PD-1 mAb plus lenvatinib had enhanced antitumor activity compared with anti-PD-1 mAb plus axitinib. Flow-cytometry analysis showed that lenvatinib decreased the population of tumor-associated macrophages and increased that of interferon (IFN) γ-positive CD8+ T cells. Activation of FGFR signaling inhibited the IFNγ-stimulated JAK/STAT signaling pathway and decreased expression of its target genes, including B2M, CXCL10, and PD-L1. Furthermore, inhibition of FGFR signaling by lenvatinib restored the tumor response to IFNγ stimulation in mouse and human RCC cell lines. These preclinical results reveal novel roles of tumor FGFR signaling in the regulation of cancer immunity through inhibition of the IFNγ pathway, and the inhibitory activity of lenvatinib against FGFRs likely contributes to the enhanced antitumor activity of combination treatment comprising lenvatinib plus anti-PD-1 mAb.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2426
  19. Nat Rev Gastroenterol Hepatol. 2021 Nov 08.
    Decoding therapy resistance in liver tumours: a giant leap.
    Chantal Desdouets, Amaia Lujambio.
      
    DOI:  https://doi.org/10.1038/s41575-021-00550-1
  20. Cancer Res. 2021 Nov 11. pii: canres.3054.2021. [Epub ahead of print]
    Myeloid-cell derived oxidized lipids and regulation of the tumor microenvironment.
    Kristin C Hicks, Yulia Y Tyurina, Valerian E Kagan, Dmitry I Gabrilovich.
      Immune suppressive myeloid cells play a major role in cancer by negatively regulating immune responses, promoting tumor progression, and limiting the efficacy of cancer immunotherapy. Immune suppression is mediated by various mechanisms dependent upon the type of myeloid cell involved. In recent years, a more universal mechanism of immune suppressive activity of myeloid cells has emerged: generation of oxidized lipids. Oxidized lipids accumulate in all types of myeloid cells and are often transferred between cells. In this review, we discuss mechanisms involved in the generation and biological role of myeloid cell-derived oxidized lipids in cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3054
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:29.