bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2022‒03‒27
35 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm.
  2. Seed or soil: Tracing the immune subsets in metastatic tumors.
  3. Bcl-xL enforces a slow-cycling state necessary for survival in the nutrient-deprived microenvironment of pancreatic cancer.
  4. Targeting CAFs to overcome anticancer therapeutic resistance.
  5. CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity.
  6. Drivers of intrinsic resistance.
  7. Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression.
  8. GIT1 protects against breast cancer growth through negative regulation of Notch.
  9. MAPK signalling-induced phosphorylation and subcellular translocation of PDHE1α promotes tumour immune evasion.
  10. Loss of H3K27 trimethylation promotes radiotherapy resistance in medulloblastoma and induces an actionable vulnerability to BET inhibition.
  11. Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML.
  12. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
  13. Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors.
  14. Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation.
  15. Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8.
  16. Central nervous system immune interactome is function of cancer lineage, tumor microenvironment and STAT3 expression.
  17. Molecular diagnosis and targeted treatment of advanced follicular cell-derived thyroid cancer in the precision medicine era.
  18. Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer.
  19. Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion.
  20. Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression.
  21. Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells.
  22. Phosphorylation of SHP2 at Tyr62 enables acquired resistance to SHP2 allosteric inhibitors in FLT3-ITD-driven AML.
  23. Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy.
  24. Awakening KDM5B to defeat leukemia.
  25. Targeting ferroptosis as a vulnerability in cancer.
  26. HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation.
  27. PTEN loss drives resistance to the neddylation inhibitor MLN4924 in glioblastoma and can be overcome with TOP2A inhibitors.
  28. What cancer survivors can teach cancer researchers.
  29. A Cell Double-Barcoding System for Quantitative Evaluation of Primary Tumors and Metastasis in Animals That Uncovers Clonal-Specific Anti-Cancer Drug Effects.
  30. The N6-methyladenosine modification of circALG1 promotes the metastasis of colorectal cancer mediated by the miR-342-5p/PGF signalling pathway.
  31. Searching for Synergy: Chemotherapy and Checkpoint Inhibitors.
  32. Forkhead box transcription factors: double-edged swords in cancer.
  33. Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer.
  34. The landscape of receptor-mediated precision cancer combination therapy via a single-cell perspective.
  35. Genomically Metastatic, but Surgically Curable?
  1. Trends Cancer. 2022 Mar 17. pii: S2405-8033(22)00040-1. [Epub ahead of print]
    Integrating mutational and nonmutational mechanisms of acquired therapy resistance within the Darwinian paradigm.
    Robert Vander Velde, Sydney Shaffer, Andriy Marusyk.
      Mutational processes and nongenetic phenotypic state transitions represent distinct paradigms for understanding acquired resistance to targeted therapies. While ample empirical evidence supports both paradigms, they are typically viewed as mutually exclusive. However, a growing body of evidence points to the multifactorial nature of resistance, where resistant tumor cell phenotypes integrate the influence of multiple mutational and epigenetic changes. This leads to growing calls for a conceptual framework capable of incorporating the effects of genetic and nongenetic mechanisms. Here, we argue that the original Darwinian paradigm centered on the concept of natural selection, rather than its mutation-centric reinterpretation, might provide the optimal backbone for a much-needed synthesis.
    Keywords:  Darwinian evolution; acquired resistance; cellular reprogramming; targeted therapy
    DOI:  https://doi.org/10.1016/j.trecan.2022.02.004
  2. Cancer Cell. 2022 Mar 15. pii: S1535-6108(22)00116-7. [Epub ahead of print]
    Seed or soil: Tracing the immune subsets in metastatic tumors.
    Xuexin Yu, Bo Li.
      Mapping the tumor-infiltrating immune subsets to an origin of malignancy or tissue niche is important for designing effective immunotherapies, yet it remains a challenging task. In this issue of Cancer Cell, Liu et al. pieced together this puzzle through a comprehensive single-cell analysis of colorectal cancer patients with liver metastases.
    DOI:  https://doi.org/10.1016/j.ccell.2022.03.001
  3. Cancer Res. 2022 Mar 22. pii: canres.CAN-22-0431-E.2022. [Epub ahead of print]
    Bcl-xL enforces a slow-cycling state necessary for survival in the nutrient-deprived microenvironment of pancreatic cancer.
    Yogev Sela, Jinyang Li, Shivahamy Maheswaran, Robert J Norgard, Salina Yuan, Maimon E Hubbi, Miriam Doepner, Jimmy P Xu, Elaine S Ho, Clementina Mesaros, Colin Sheehan, Grace Croley, Alexander Muir, Ian A Blair, Ophir Shalem, Chi V Dang, Ben Z Stanger.
      Solid tumors possess heterogeneous metabolic microenvironments where oxygen and nutrient availability are plentiful ('fertile regions') or scarce ('arid regions'). While cancer cells residing in fertile regions proliferate rapidly, most cancer cells in vivo reside in arid regions and exhibit a slow-cycling state that renders them chemoresistant. Here, we developed an in vitro system enabling systematic comparison between these populations via transcriptome analysis, metabolomic profiling, and whole-genome CRISPR screening. Metabolic deprivation led to pronounced transcriptional and metabolic reprogramming, resulting in decreased anabolic activities and distinct vulnerabilities. Reductions in anabolic, energy-consuming activities, particularly cell proliferation, were not simply byproducts of the metabolic challenge but rather essential adaptations. Mechanistically, Bcl-xL played a central role in the adaptation to nutrient and oxygen deprivation. In this setting, Bcl-xL protected quiescent cells from the lethal effects of cell cycle entry in the absence of adequate nutrients. Moreover, inhibition of Bcl-xL combined with traditional chemotherapy had a synergistic anti-tumor effect that targeted cycling cells. Bcl-xL expression was strongly associated with poor patient survival despite being confined to the slow-cycling fraction of human pancreatic cancer cells. These findings provide a rationale for combining traditional cancer therapies that target rapidly cycling cells with those that target quiescent, chemoresistant cells associated with nutrient and oxygen deprivation.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0431
  4. Trends Cancer. 2022 Mar 21. pii: S2405-8033(22)00055-3. [Epub ahead of print]
    Targeting CAFs to overcome anticancer therapeutic resistance.
    Phei Er Saw, Jianing Chen, Erwei Song.
      The view of cancer as a tumor cell-centric disease is now replaced by our understanding of the interconnection and dependency of tumor stroma. Cancer-associated fibroblasts (CAFs), the most abundant stromal cells in the tumor microenvironment (TME), are involved in anticancer therapeutic resistance. As we unearth more solid evidence on the link between CAFs and tumor progression, we gain insight into the role of CAFs in establishing resistance to cancer therapies. Herein, we review the origin, heterogeneity, and function of CAFs, with a focus on how CAF subsets can be used as biomarkers and can contribute to therapeutic resistance in cancer. We also depict current breakthroughs in targeting CAFs to overcome anticancer therapeutic resistance and discuss emerging CAF-targeting modalities.
    Keywords:  CAF-specific targeting; cancer-associated fibroblast; resistance; tumor ecosystem
    DOI:  https://doi.org/10.1016/j.trecan.2022.03.001
  5. Nat Commun. 2022 Mar 25. 13(1): 1606
    CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity.
    Julia Joung, Paul C Kirchgatterer, Ankita Singh, Jang H Cho, Suchita P Nety, Rebecca C Larson, Rhiannon K Macrae, Rebecca Deasy, Yuen-Yi Tseng, Marcela V Maus, Feng Zhang.
      The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (CD274 (PD-L1), MCL1, JUNB, and B3GNT2) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway. JUNB encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway. B3GNT2 encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-29205-8
  6. Nat Chem Biol. 2022 Mar 24.
    Drivers of intrinsic resistance.
    Kris C Wood.
      
    DOI:  https://doi.org/10.1038/s41589-022-00980-1
  7. Nat Commun. 2022 Mar 24. 13(1): 1592
    Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression.
    Seungyeul Yoo, Abhilasha Sinha, Dawei Yang, Nasser K Altorki, Radhika Tandon, Wenhui Wang, Deebly Chavez, Eunjee Lee, Ayushi S Patel, Takashi Sato, Ranran Kong, Bisen Ding, Eric E Schadt, Hideo Watanabe, Pierre P Massion, Alain C Borczuk, Jun Zhu, Charles A Powell.
      Here we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma.
    DOI:  https://doi.org/10.1038/s41467-022-29230-7
  8. Nat Commun. 2022 Mar 22. 13(1): 1537
    GIT1 protects against breast cancer growth through negative regulation of Notch.
    Songbai Zhang, Ayako Miyakawa, Malin Wickström, Cecilia Dyberg, Lauri Louhivuori, Manuel Varas-Godoy, Kati Kemppainen, Shigeaki Kanatani, Dagmara Kaczynska, Ivar Dehnisch Ellström, Lotta Elfman, Pauliina Kronqvist, Heli Repo, Katsuhiko Mikoshiba, Cecilia Sahlgren, John Inge Johnsen, Per Uhlén.
      Hyperactive Notch signalling is frequently observed in breast cancer and correlates with poor prognosis. However, relatively few mutations in the core Notch signalling pathway have been identified in breast cancer, suggesting that as yet unknown mechanisms increase Notch activity. Here we show that increased expression levels of GIT1 correlate with high relapse-free survival in oestrogen receptor-negative (ER(-)) breast cancer patients and that GIT1 mediates negative regulation of Notch. GIT1 knockdown in ER(-) breast tumour cells increased signalling downstream of Notch and activity of aldehyde dehydrogenase, a predictor of poor clinical outcome. GIT1 interacts with the Notch intracellular domain (ICD) and influences signalling by inhibiting the cytoplasm-to-nucleus transport of the Notch ICD. In xenograft experiments, overexpression of GIT1 in ER(-) cells prevented or reduced Notch-driven tumour formation. These results identify GIT1 as a modulator of Notch signalling and a guardian against breast cancer growth.
    DOI:  https://doi.org/10.1038/s41467-022-28631-y
  9. Nat Metab. 2022 Mar 21.
    MAPK signalling-induced phosphorylation and subcellular translocation of PDHE1α promotes tumour immune evasion.
    Yajuan Zhang, Ming Zhao, Hong Gao, Guanzhen Yu, Yun Zhao, Feng Yao, Weiwei Yang.
      Tumour cells utilize multiple strategies to evade the immune system, but the underlying metabolic mechanisms remain poorly understood. The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl-coenzyme A in mitochondria, thereby linking glycolysis to the ricarboxylic acid cycle. Here we show that the PDH complex E1 subunit α (PDHE1α) is also located in the cytosol. Cytosolic PDHE1α interacts with IKKβ and protein phosphatase 1B, thereby facilitating the inhibition of the NF-κB pathway. Cytosolic PDHE1α can be phosphorylated at S327 by ERK2 and translocated into mitochondria. Decreased cytosolic PDHE1α levels restore NF-κB signalling, whereas increased mitochondrial PDHE1α levels drive α-ketoglutarate production and promote reactive oxygen species detoxification. Synergistic activation of NF-κB and reactive oxygen species detoxification promotes tumour cell survival and enhances resistance to cytotoxic lymphocytes. Consistently, low levels of PDHE1α phosphorylation are associated with poor prognosis of patients with lung cancer. Our findings show a mechanism through which phosphorylation-dependent subcellular translocation of PDHE1α promotes tumour immune evasion.
    DOI:  https://doi.org/10.1038/s42255-022-00543-7
  10. Cancer Res. 2022 Mar 22. pii: canres.0871.2021. [Epub ahead of print]
    Loss of H3K27 trimethylation promotes radiotherapy resistance in medulloblastoma and induces an actionable vulnerability to BET inhibition.
    Nishanth N Gabriel, Kumaresh Balaji, Kay Jayachandran, Matthew Inkman, Jin Zhang, Sonika Dahiya, Michael Goldstein.
      Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic, and transcriptional profiling. Radiation is used for treating medulloblastoma regardless of the subgroup. A better understanding of the molecular pathways determining radiotherapy response could help improve medulloblastoma treatment. Here, we investigated the role of the EZH2-dependent histone H3K27 trimethylation in radiotherapy response in medulloblastoma. The tumors in 47.2% of group 3 and 4 medulloblastoma patients displayed H3K27me3 deficiency. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates, and poor overall survival. In H3K27me3-deficient medulloblastoma cells, an epigenetic switch from H3K27me3 to H3K27ac occurred at specific genomic loci, altering the transcriptional profile. The resulting upregulation of EPHA2 stimulated excessive activation of the pro-survival AKT signaling pathway, leading to radiotherapy resistance. BET inhibition overcame radiation resistance in H3K27me3-deficient medulloblastoma cells by suppressing H3K27ac levels, blunting EPHA2 overexpression, and mitigating excessive AKT signaling. Additionally, BET inhibition sensitized medulloblastoma cells to radiation by enhancing the apoptotic response through suppression of Bcl-xL and upregulation of Bim. This work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. Based on these findings, we propose an epigenetically guided treatment approach targeting radiotherapy resistance in medulloblastoma patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0871
  11. Cancer Discov. 2022 Mar 21. pii: candisc.1145.2020. [Epub ahead of print]
    Epigenetic activation of plasmacytoid DC drives IFNAR-dependent therapeutic differentiation of AML.
    Jessica M Salmon, Izabela Todorovski, Kym L Stanley, Claudia Bruedigam, Conor J Kearney, Luciano G Martelotto, Fernando J Rossello, Timothy Semple, Gisela Mir Arnau, Magnus Zethoven, Michael Bots, Stefan Bjelosevic, Leonie A Cluse, Peter J Fraser, Veronique Litalien, Eva Vidacs, Kate McArthur, Antony Y Matthews, Elise Gressier, Nicole A de Weerd, Jens Lichte, Madison J Kelly, Simon J Hogg, Paul J Hertzog, Lev M Kats, Stephin J Vervoort, Daniel D De Carvalho, Stefanie Scheu, Sammy Bedoui, Benjamin T Kile, Steven W Lane, Andrew C Perkins, Andrew H Wei, Pilar M Dominguez, Ricky W Johnstone.
      Pharmacological inhibition of epigenetic enzymes can have therapeutic benefit against hematological malignancies. In addition to affecting tumor cell growth and proliferation, these epigenetic agents may induce anti-tumor immunity. Here we discovered a novel immuno-regulatory mechanism through inhibition of histone deacetylases (HDACs). In models of AML, leukemia cell differentiation and therapeutic benefit mediated by the HDAC inhibitor panobinostat required activation of the type I interferon (IFN) pathway. Plasmacytoid dendritic cells (pDCs) produced type I IFN after panobinostat treatment, through transcriptional activation of IFN genes concomitant with increased H3K27 acetylation at these loci. Depletion of pDCs abrogated panobinostat-mediated induction of type I IFN signaling in leukemia cells and impaired therapeutic efficacy, while combined treatment of panobinostat and IFN improved outcomes in pre-clinical models. These discoveries offer a new therapeutic approach for AML and demonstrate that epigenetic rewiring of pDCs enhances anti-tumor immunity, opening the possibility of exploiting this approach for immunotherapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1145
  12. Nat Commun. 2022 Mar 21. 13(1): 1503
    A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
    Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi S Shah, Sylwia A Stopka, Andrew J Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E Capen, Enzo Medico, Murat Cetinbas, Ruslan I Sadreyev, Dennis Brown, Miguel N Rivera, Anna Sapino, David T Breault, Nathalie Y R Agar, Raul Mostoslavsky.
      Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.
    DOI:  https://doi.org/10.1038/s41467-022-29085-y
  13. Nat Commun. 2022 Mar 24. 13(1): 1588
    Targeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors.
    Peitao Zhang, Haixia Guan, Shukai Yuan, Huili Cheng, Jian Zheng, Zhenlei Zhang, Yifan Liu, Yang Yu, Zhaowei Meng, Xiangqian Zheng, Li Zhao.
      MAPK signaling inhibitor (MAPKi) therapies show limited efficacy for advanced thyroid cancers despite constitutive activation of the signaling correlates with disease recurrence and persistence. Understanding how BRAF pathway stimulates tumorigenesis could lead to new therapeutic targets. Here, through genetic and pathological approaches, we demonstrate that BRAFV600E promotes thyroid cancer development by increasing myeloid-derived suppressor cells (MDSCs) penetrance. This BRAFV600E-induced immune suppression involves re-activation of the developmental factor TBX3, which in turn up-regulates CXCR2 ligands in a TLR2-NFκB dependent manner, leading to MDSCs recruitment into the tumor microenvironment. CXCR2 inhibition or MDSCs repression improves MAPKi therapy effect. Clinically, high TBX3 expression correlates with BRAFV600E mutation and increased CXCR2 ligands, along with abundant MDSCs infiltration. Thus, our study uncovers a BRAFV600E-TBX3-CXCLs-MDSCs axis that guides patient stratification and could be targeted to improve the efficacy of MAPKi therapy in advanced thyroid cancer patients.
    DOI:  https://doi.org/10.1038/s41467-022-29000-5
  14. Oncogene. 2022 Mar 23.
    Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation.
    Margaux Sala, Nathalie Allain, Mélanie Moreau, Arnaud Jabouille, Elodie Henriet, Aya Abou-Hammoud, Arnaud Uguen, Sylvaine Di-Tommaso, Cyril Dourthe, Anne-Aurélie Raymond, Jean-William Dupuy, Emilie Gerard, Nathalie Dugot-Senant, Benoit Rousseau, Jean-Phillipe Merlio, Anne Pham-Ledart, Béatrice Vergier, Sophie Tartare-Deckert, Violaine Moreau, Frédéric Saltel.
      Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.
    DOI:  https://doi.org/10.1038/s41388-022-02266-1
  15. Sci Adv. 2022 Mar 25. 8(12): eabh4050
    Radiotherapy orchestrates natural killer cell dependent antitumor immune responses through CXCL8.
    Thomas Walle, Joscha A Kraske, Boyu Liao, Bénédicte Lenoir, Carmen Timke, Emilia von Bohlen Und Halbach, Florian Tran, Paul Griebel, Dorothee Albrecht, Azaz Ahmed, Meggy Suarez-Carmona, Alejandro Jiménez-Sánchez, Tizian Beikert, Alexandra Tietz-Dahlfuß, Ayse Nur Menevse, Gabriele Schmidt, Manuela Brom, Jens H W Pahl, Wiebke Antonopoulos, Matthias Miller, Ramon Lopez Perez, Felix Bestvater, Nathalia A Giese, Philipp Beckhove, Philip Rosenstiel, Dirk Jäger, Oliver Strobel, Dana Pe'er, Niels Halama, Jürgen Debus, Adelheid Cerwenka, Peter E Huber.
      Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56dim-like cytotoxic transcriptomic states. In experimental models, NF-κB and mTOR orchestrated radiation-induced CXCL8 secretion from tumor cells with senescence features causing directional migration of CD56dim NK cells, thus linking senescence-associated CXCL8 release to innate immune surveillance of human tumors. Moreover, combined high-dose radiotherapy and adoptive NK cell transfer improved tumor control over monotherapies in xenografted mice, suggesting NK cells combined with radiotherapy as a rational cancer treatment strategy.
    DOI:  https://doi.org/10.1126/sciadv.abh4050
  16. JCI Insight. 2022 Mar 22. pii: e157612. [Epub ahead of print]
    Central nervous system immune interactome is function of cancer lineage, tumor microenvironment and STAT3 expression.
    Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M Sonabend, Craig Horbinski, Roel Verhaak, Anand Shankar, Santhoshi N Krishnan, Frederick S Varn, Víctor A Arrieta, Pravesh Gupta, Sherise D Ferguson, Jason T Huse, Gregory N Fuller, James P Long, Daniel E Winkowski, Benjamin A Freiberg, C David James, Leonidas C Platanias, Maciej S Lesniak, Jared K Burks, Amy B Heimberger.
      INTRODUCTION: Immune cell profiling of primary and metastatic central nervous system (CNS) tumors has been focused on the tumor, not the tumor microenvironment (TME), or have been analyzed via biopsies.METHODS: En bloc resections of glioma (n=10) and lung metastasis (n=10) underwent tissue segmentation and high dimension opal 7-color multiplex imaging. Single cell RNA analyses inferred immune cell functionality.
    RESULTS: Within gliomas, T cells were localized to the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163+ macrophages were evident throughout the TME of metastatic tumors, whereas in gliomas, CD68+, CD11c+CD68+, and CD11c+CD68+CD163+ cell subtypes, were commonly observed. In lung metastases, T cells interact with CD163+ macrophages as dyads and clusters at the brain-tumor interface and within the tumor itself, and as clusters within the necrotic core. In contrast, gliomas typically lack dyad and cluster interactions, except for T cell-CD68+cell dyads within the tumor. Analysis of transcriptomic data in glioblastomas revealed that innate immune cells express both pro-inflammatory and immune suppressive gene signatures.
    CONCLUSION: Our results show that immunosuppressive macrophages are abundant within the TME, and that the immune cell interactome between cancer lineages is distinct. Further, these data provide information for evaluating the role of different immune cell populations in brain tumor growth and therapeutic responses.
    Keywords:  Brain cancer; Immunology; Innate immunity; Oncology; T cells
    DOI:  https://doi.org/10.1172/jci.insight.157612
  17. Cancer Treat Rev. 2022 Mar 15. pii: S0305-7372(22)00044-5. [Epub ahead of print]106 102380
    Molecular diagnosis and targeted treatment of advanced follicular cell-derived thyroid cancer in the precision medicine era.
    Jaume Capdevila, Ahmad Awada, Dagmar Führer-Sakel, Sophie Leboulleux, Patrick Pauwels.
      Most malignant thyroid tumours are initially treated with surgery or a combination of surgery and radioactive iodine (RAI) therapy. However, in patients with metastatic disease, many tumours become refractory to RAI, and these patients require alternative treatments, such as locoregional therapies and/or systemic treatment with multikinase inhibitors. Improvements in our understanding of the genetic alterations that occur in thyroid cancer have led to the discovery of several targeted therapies with clinical efficacy. These alterations include NTRK (neurotrophic tyrosine receptor kinase) gene fusions, with the tropomyosin receptor kinase inhibitors larotrectinib and entrectinib both approved by the European Medicines Agency and in other markets worldwide. Inhibitors of aberrant proteins resulting from alterations in RET (rearranged during transfection) and BRAF (B-Raf proto-oncogene) have also shown promising efficacy, and so far have received approval by the US Food and Drug Administration. Selpercatinib, a RET kinase inhibitor, was approved for use in Europe in early 2021. With the discovery of multiple actionable targets, it is imperative that effective testing strategies for these genetic alterations are integrated into the diagnostic armamentarium to ensure that patients who could potentially benefit from targeted treatments are identified. In this review, we offer our recommendations on the optimal testing strategies for detecting genetic alterations in thyroid cancer that have the potential to be targeted by molecular therapy. We also discuss the future of treatments for thyroid cancers, including the use of immune checkpoint inhibitors, and new generations of targeted treatments that are being developed to counter acquired tumour resistance.
    Keywords:  BRAF; NTRK; RET; Targeted therapy; Testing; Thyroid cancer
    DOI:  https://doi.org/10.1016/j.ctrv.2022.102380
  18. Cell. 2022 Mar 18. pii: S0092-8674(22)00201-X. [Epub ahead of print]
    Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer.
    Rodrigo Nalio Ramos, Yoann Missolo-Koussou, Yohan Gerber-Ferder, Christian P Bromley, Mattia Bugatti, Nicolas Gonzalo Núñez, Jimena Tosello Boari, Wilfrid Richer, Laurie Menger, Jordan Denizeau, Christine Sedlik, Pamela Caudana, Fiorella Kotsias, Leticia L Niborski, Sophie Viel, Mylène Bohec, Sonia Lameiras, Sylvain Baulande, Laëtitia Lesage, André Nicolas, Didier Meseure, Anne Vincent-Salomon, Fabien Reyal, Charles-Antoine Dutertre, Florent Ginhoux, Lene Vimeux, Emmanuel Donnadieu, Bénédicte Buttard, Jérôme Galon, Santiago Zelenay, William Vermi, Pierre Guermonprez, Eliane Piaggio, Julie Helft.
      Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.
    Keywords:  CD8(+) T lymphocytes; FOLR2; TREM2; breast cancer; single-cell RNA sequencing; tissue-resident macrophages
    DOI:  https://doi.org/10.1016/j.cell.2022.02.021
  19. Nat Commun. 2022 Mar 21. 13(1): 1511
    Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion.
    Nian Jiang, Bowen Xie, Wenwu Xiao, Ming Fan, Shanxiu Xu, Yixin Duan, Yamah Hamsafar, Angela C Evans, Jie Huang, Weibing Zhou, Xuelei Lin, Ningrong Ye, Siyi Wanggou, Wen Chen, Di Jing, Ruben C Fragoso, Brittany N Dugger, Paul F Wilson, Matthew A Coleman, Shuli Xia, Xuejun Li, Lun-Quan Sun, Arta M Monjazeb, Aijun Wang, William J Murphy, Hsing-Jien Kung, Kit S Lam, Hong-Wu Chen, Jian Jian Li.
      Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A-/-, CPT2-/-, ACAD9-/- cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-29137-3
  20. EMBO J. 2022 Mar 21. e110466
    Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression.
    Victoire Gouirand, Tristan Gicquel, Evan C Lien, Emilie Jaune-Pons, Quentin Da Costa, Pascal Finetti, Elodie Metay, Camille Duluc, Jared R Mayers, Stephane Audebert, Luc Camoin, Laurence Borge, Marion Rubis, Julie Leca, Jeremy Nigri, François Bertucci, Nelson Dusetti, Juan Lucio Iovanna, Richard Tomasini, Ghislain Bidaut, Fabienne Guillaumond, Matthew G Vander Heiden, Sophie Vasseur.
      Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.
    Keywords:  HMGCL; ketone bodies; metastasis; pancreatic cancer; β-hydroxybutyrate
    DOI:  https://doi.org/10.15252/embj.2021110466
  21. Mol Cell. 2022 Mar 16. pii: S1097-2765(22)00207-6. [Epub ahead of print]
    Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells.
    Jia Xiong, Jia He, Jun Zhu, Jiongli Pan, Weijie Liao, Hongying Ye, Haofei Wang, Yinjing Song, Yue Du, Bijun Cui, Maoguang Xue, Wanling Zheng, Xiangxing Kong, Kai Jiang, Kefeng Ding, Lihua Lai, Qingqing Wang.
      Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N6-methyladenosine (m6A) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated m6A modification on Jak1 mRNA in TIMs, the m6A-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA m6A modification for promoting the immunosuppressive capacity of TIMs.
    Keywords:  JAK-STAT; METTL3; lactate; lactylation; m(6)A; tumor-infiltrating myeloid cells
    DOI:  https://doi.org/10.1016/j.molcel.2022.02.033
  22. Cancer Res. 2022 Mar 21. pii: canres.0548.2021. [Epub ahead of print]
    Phosphorylation of SHP2 at Tyr62 enables acquired resistance to SHP2 allosteric inhibitors in FLT3-ITD-driven AML.
    Anamarija Pfeiffer, Giulia Franciosa, Marie Locard-Paulet, Ilaria Piga, Kristian Reckzeh, Vidyasiri Vemulapalli, Stephen C Blacklow, Kim Theilgaard-Mönch, Lars J Jensen, Jesper V Olsen.
      The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTK). SHP2 is required for full RAS-ERK activation to promote cell proliferation and survival programs. Allosteric SHP2 inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and are currently being tested in clinical trials for tumors with overactivation of the RAS/ERK pathway, alone and in various drug combinations. In this study, we established cells with acquired resistance to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. Label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics of these resistant models demonstrated that AML cells can restore phosphorylated ERK (pERK) in the presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induced tyrosine phosphorylation and feedback-driven activation of the FLT3 receptor, which in turn phosphorylated SHP2 on tyrosine 62. This phosphorylation stabilized SHP2 in its open conformation, preventing SHP099 binding and conferring resistance. Combinatorial inhibition of SHP2 and MEK or FLT3 prevented pERK rebound and resistant cell growth. The same mechanism was observed in a FLT3-mutated B-ALL cell line and in the inv(16)/KitD816Y AML mouse model, but allosteric inhibition of Shp2 did not impair the clonogenic ability of normal bone marrow progenitors. Together, these results support the future use of SHP2 inhibitor combinations for clinical applications.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0548
  23. J Hematol Oncol. 2022 Mar 24. 15(1): 34
    Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy.
    Yangfu Jiang, Hongying Zhang, Jiao Wang, Yongliang Liu, Ting Luo, Hui Hua.
      Cancer microenvironment is critical for tumorigenesis and cancer progression. The extracellular matrix (ECM) interacts with tumor and stromal cells to promote cancer cells proliferation, migration, invasion, angiogenesis and immune evasion. Both ECM itself and ECM stiffening-induced mechanical stimuli may activate cell membrane receptors and mechanosensors such as integrin, Piezo1 and TRPV4, thereby modulating the malignant phenotype of tumor and stromal cells. A better understanding of how ECM stiffness regulates tumor progression will contribute to the development of new therapeutics. The rapidly expanding evidence in this research area suggests that the regulators and effectors of ECM stiffness represent potential therapeutic targets for cancer. This review summarizes recent work on the regulation of ECM stiffness in cancer, the effects of ECM stiffness on tumor progression, cancer immunity and drug resistance. We also discuss the potential targets that may be druggable to intervene ECM stiffness and tumor progression. Based on these advances, future efforts can be made to develop more effective and safe drugs to interrupt ECM stiffness-induced oncogenic signaling, cancer progression and drug resistance.
    Keywords:  Cancer; Cancer therapy; Drug resistance; ECM stiffness; Extracellular matrix; Mechanotransducer; Piezo
    DOI:  https://doi.org/10.1186/s13045-022-01252-0
  24. Proc Natl Acad Sci U S A. 2022 Mar 29. 119(13): e2202245119
    Awakening KDM5B to defeat leukemia.
    Lok Hei Chan, Qin Yan.
      
    DOI:  https://doi.org/10.1073/pnas.2202245119
  25. Nat Rev Cancer. 2022 Mar 25.
    Targeting ferroptosis as a vulnerability in cancer.
    Guang Lei, Li Zhuang, Boyi Gan.
      Ferroptosis is an iron-dependent form of regulated cell death that is triggered by the toxic build-up of lipid peroxides on cellular membranes. In recent years, ferroptosis has garnered enormous interest in cancer research communities, partly because it is a unique cell death modality that is mechanistically and morphologically different from other forms of cell death, such as apoptosis, and therefore holds great potential for cancer therapy. In this Review, we summarize the current understanding of ferroptosis-inducing and ferroptosis defence mechanisms, dissect the roles and mechanisms of ferroptosis in tumour suppression and tumour immunity, conceptualize the diverse vulnerabilities of cancer cells to ferroptosis, and explore therapeutic strategies for targeting ferroptosis in cancer.
    DOI:  https://doi.org/10.1038/s41568-022-00459-0
  26. Oncogene. 2022 Mar 22.
    HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation.
    Huajie Song, Jianqun Wang, Xiaojing Wang, Boling Yuan, Dan Li, Anpei Hu, Yanhua Guo, Shuang Cai, Shikai Jin, Yi Zhou, Qilan Li, Guo Chen, Haiyang Gao, Liduan Zheng, Qiangsong Tong.
      Cancer stem cells play crucial roles in tumorigenesis and aggressiveness, while regulatory mechanisms in neuroblastoma (NB), a pediatric extracranial malignancy with highest incidence, are still unknown. Herein, a small 51-amino acid peptide (sPEP1) encoded by hepatocyte nuclear factor 4 alpha antisense RNA 1 (HNF4A-AS1) was identified in tumor tissues and cells, which facilitated self-renewal and aggressiveness of NB stem cells. MiRNA-409-5p interacted with HNF4A-AS1 to facilitate sPEP1 translation via recruiting eukaryotic translation initiation factor 3 subunit G, while sPEP1 repressed serum deprivation-induced senescence and promoted sphere formation, growth, or metastasis of NB stem cells. Mechanistically, sPEP1 directly interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) to facilitate its binding to SMAD family member 4 (SMAD4), resulting in repression of SMAD4 transactivation and transcriptional upregulation of stem cell genes associated with tumor progression. Rescue experiments revealed that sPEP1 exerted oncogenic roles via facilitating physical interaction between eEF1A1 and SMAD4. Notably, knockdown of sPEP1 significantly repressed the self-renewal and metastasis of NB stem cells in vivo. High sPEP1 or eEF1A1 levels in clinical NB tissues were linked to poor patients' survival. These findings suggest that HNF4A-AS1-encoded sPEP1 promotes self-renewal and aggressive features of NB stem cells by eEF1A1-repressed SMAD4 transactivation.
    DOI:  https://doi.org/10.1038/s41388-022-02271-4
  27. Neuro Oncol. 2022 Mar 19. pii: noac067. [Epub ahead of print]
    PTEN loss drives resistance to the neddylation inhibitor MLN4924 in glioblastoma and can be overcome with TOP2A inhibitors.
    Shayesteh R Ferdosi, Brett Taylor, Matthew Lee, Nanyun Tang, Sen Peng, Rita Bybee, George Reid, Lauren Hartman, Krystine Garcia-Mansfield, Ritin Sharma, Patrick Pirrotte, Jianhui Ma, Alison D Parisian, Frank Furnari, Harshil D Dhruv, Michael E Berens.
      BACKGROUND: Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability to MLN4924 or pevonedistat (a neddylation inhibitor) in a subset of glioblastoma (GBM) preclinical models and identify biomarkers, mechanisms, and signatures of differential response.METHODS: GBM sequencing data was queried for genes associated with MLN4924 response status; candidates were validated by molecular techniques. Time-course transcriptomics and proteomics revealed processes implicated in MLN4924 response.
    RESULTS: Vulnerability to MLN4924 is associated with elevated S-phase populations, re-replication, and DNA damage. Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between sensitive and resistant models. Loss of PTEN and its nuclear functions is associated with resistance to MLN4924. Time-course proteomics identified elevated TOP2A in resistant models through treatment. TOP2A inhibitors combined with MLN4924 prove synergistic.
    CONCLUSIONS: We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.
    Keywords:  DNA Replication; Glioblastoma (GBM); Multi-Omics; Neddylation; PTEN
    DOI:  https://doi.org/10.1093/neuonc/noac067
  28. Nat Rev Cancer. 2022 Mar 23.
    What cancer survivors can teach cancer researchers.
    Victoria J Forster.
      
    DOI:  https://doi.org/10.1038/s41568-022-00468-z
  29. Cancers (Basel). 2022 Mar 08. pii: 1381. [Epub ahead of print]14(6):
    A Cell Double-Barcoding System for Quantitative Evaluation of Primary Tumors and Metastasis in Animals That Uncovers Clonal-Specific Anti-Cancer Drug Effects.
    Arkadi Hesin, Santosh Kumar, Valid Gahramanov, Maria Becker, Maria Vilenchik, Ilya Alexandrov, Julia Yaglom, Michael Y Sherman.
      Imaging in monitoring metastasis in mouse models has low sensitivity and is not quantitative. Cell DNA barcoding, demonstrating high sensitivity and resolution, allows monitoring effects of drugs on the number of tumor and metastatic clones. However, this technology is not suitable for comparison of sizes of metastatic clones in different animals, for example, drug treated and untreated, due to high biological and technical variability upon tumor and metastatic growth and isolation of barcodes from tissue DNA. However, both numbers of clones and their sizes are critical parameters for analysis of drug effects. Here we developed a modification of the barcoding approach for monitoring drug effects on tumors and metastasis that is quantitative, highly sensitive and highly reproducible. This novel cell double-barcoding system allows simultaneously following the fate of two or more cell variants or cell lines in xenograft models in vivo, and also following the fates of individual clones within each of these populations. This system allows comparing effects of drugs on different cell populations and thus normalizing drug effects by drug-resistant lines, which corrects for both biological and technical variabilities and significantly increases the reproducibility of results. Using this barcoding system, we uncovered that effects of a novel DYRK1B kinase inhibitor FX9847 on primary tumors and metastasis is clone-dependent, while a distinct drug osimertinib demonstrated clone-independent effects on cancer cell populations. Overall, a cell double-barcoding approach can significantly enrich our understanding of drug effects in basic research and preclinical studies.
    Keywords:  cell barcoding; drug effects; metastasis; preclinical studies; xenograft
    DOI:  https://doi.org/10.3390/cancers14061381
  30. Mol Cancer. 2022 Mar 19. 21(1): 80
    The N6-methyladenosine modification of circALG1 promotes the metastasis of colorectal cancer mediated by the miR-342-5p/PGF signalling pathway.
    Changwei Lin, Min Ma, Yi Zhang, Liang Li, Fei Long, Canbin Xie, Hua Xiao, Teng Liu, Buning Tian, Kaiyan Yang, Yihang Guo, Miao Chen, Jin Chou, Ni Gong, Xiaorong Li, Gui Hu.
      BACKGROUND: Previous studies have shown that the N6-methyladenosine (m6A) modification enhances the binding ability of mRNAs/long noncoding RNAs (lncRNAs) to microRNAs (miRNAs), but the impact of this modification on the competitive endogenous RNA (ceRNA) function of circular RNAs (circRNAs) is unclear.METHODS: We used a human circRNA microarray to detect the expression profiles of circRNAs in 3 pairs of cancer and paracancerous tissues from patients with colorectal cancer (CRC) and 3 pairs of peripheral blood specimens from patients with CRC and healthy individuals. The circRNAs highly expressed in both peripheral blood and tumour tissues of patients with CRC, including circALG1, were screened. A quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis of an expanded sample size was performed to detect the expression level of circALG1 in peripheral blood and tumour tissues of patients with CRC and determine its correlation with clinicopathological features, and circRNA loop-forming validation and stability assays were then conducted. Transwell assays and a nude mouse cancer metastasis model were used to study the function of circALG1 in CRC and the role of altered m6A modification levels on the regulation of circALG1 function. qRT-PCR, western blot (WB), Transwell, RNA-binding protein immunoprecipitation (RIP), RNA antisense purification (RAP), and dual-luciferase reporter gene assays were performed to analyse the ceRNA mechanism of circALG1 and the effect of the m6A modification of circALG1 on the ceRNA function of this circRNA.
    RESULTS: CircALG1 was highly expressed in both the peripheral blood and tumour tissues of patients with CRC and was closely associated with CRC metastasis. CircALG1 overexpression promoted the migration and invasion of CRC cells, and circALG1 silencing and reduction of the circALG1 m6A modification level inhibited CRC cell migration and invasion. In vivo experiments further confirmed the prometastatic role of circALG1 in CRC. Further mechanistic studies showed that circALG1 upregulated the expression of placental growth factor (PGF) by binding to miR-342-5p and that m6A modification enhanced the binding of circALG1 to miR-342-5p and promoted its ceRNA function.
    CONCLUSION: M6A modification enhances the binding ability of circALG1 to miR-342-5p to promote the ceRNA function of circALG1, and circALG1 could be a potential therapeutic target in and a prognostic marker for CRC.
    Keywords:  Colorectal cancer; Competitive endogenous RNA; N6-methyladenosine modification; Placental growth factor; circALG1; miR-342-5p
    DOI:  https://doi.org/10.1186/s12943-022-01560-6
  31. Clin Cancer Res. 2022 Mar 24. pii: clincanres.0335.2022. [Epub ahead of print]
    Searching for Synergy: Chemotherapy and Checkpoint Inhibitors.
    Diane Tseng, Justin F Gainor.
      Continuation of PD-1 inhibitors in combination with chemotherapy did not improve clinical outcomes for patients with non-small cell lung cancer who progressed on prior PD-1/PD-L1 inhibitor monotherapy. This highlights the need to evaluate the precise mechanisms of resistance to PD-1 axis inhibitors and explore alternative therapeutic strategies to overcome resistance.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-0335
  32. Cancer Res. 2022 Mar 22. pii: canres.3371.2021. [Epub ahead of print]
    Forkhead box transcription factors: double-edged swords in cancer.
    Maria Castaneda, Petra den Hollander, Sendurai A Mani.
      A plethora of treatment options exist for cancer therapeutics, but many are limited by side effects and either intrinsic or acquired resistance. The need for more effective targeted cancer treatment has led to the focus on forkhead box transcription factors as possible drug targets. Forkhead factors such as FOXA1 and FOXM1 are involved in hormone regulation, immune system modulation, and disease progression through their regulation of the epithelial-mesenchymal transition. Forkhead factors can influence cancer development, progression, metastasis, and drug resistance. In this review, we discuss the various roles of forkhead factors in biological processes that support cancer as well as their function as pioneering factors and their potential as targetable transcription factors in the fight against cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3371
  33. Mol Cancer. 2022 Mar 25. 21(1): 86
    Liquid biopsy at the frontier of detection, prognosis and progression monitoring in colorectal cancer.
    Hui Zhou, Liyong Zhu, Jun Song, Guohui Wang, Pengzhou Li, Weizheng Li, Ping Luo, Xulong Sun, Jin Wu, Yunze Liu, Shaihong Zhu, Yi Zhang.
      Colorectal cancer (CRC) is one of the most common cancers worldwide and a leading cause of carcinogenic death. To date, surgical resection is regarded as the gold standard by the operator for clinical decisions. Because conventional tissue biopsy is invasive and only a small sample can sometimes be obtained, it is unable to represent the heterogeneity of tumor or dynamically monitor tumor progression. Therefore, there is an urgent need to find a new minimally invasive or noninvasive diagnostic strategy to detect CRC at an early stage and monitor CRC recurrence. Over the past years, a new diagnostic concept called "liquid biopsy" has gained much attention. Liquid biopsy is noninvasive, allowing repeated analysis and real-time monitoring of tumor recurrence, metastasis or therapeutic responses. With the advanced development of new molecular techniques in CRC, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), exosomes, and tumor-educated platelet (TEP) detection have achieved interesting and inspiring results as the most prominent liquid biopsy markers. In this review, we focused on some clinical applications of CTCs, ctDNA, exosomes and TEPs and discuss promising future applications to solve unmet clinical needs in CRC patients.
    Keywords:  Circulating tumor DNA; Circulating tumor cells; Clinical application; Colorectal cancer; Exosomes; Liquid biopsy; Tumor-educated platelets
    DOI:  https://doi.org/10.1186/s12943-022-01556-2
  34. Nat Commun. 2022 Mar 25. 13(1): 1613
    The landscape of receptor-mediated precision cancer combination therapy via a single-cell perspective.
    Saba Ahmadi, Pattara Sukprasert, Rahulsimham Vegesna, Sanju Sinha, Fiorella Schischlik, Natalie Artzi, Samir Khuller, Alejandro A Schäffer, Eytan Ruppin.
      Mining a large cohort of single-cell transcriptomics data, here we employ combinatorial optimization techniques to chart the landscape of optimal combination therapies in cancer. We assume that each individual therapy can target any one of 1269 genes encoding cell surface receptors, which may be targets of CAR-T, conjugated antibodies or coated nanoparticle therapies. We find that in most cancer types, personalized combinations composed of at most four targets are then sufficient for killing at least 80% of tumor cells while sparing at least 90% of nontumor cells in the tumor microenvironment. However, as more stringent and selective killing is required, the number of targets needed rises rapidly. Emerging individual targets include PTPRZ1 for brain and head and neck cancers and EGFR in multiple tumor types. In sum, this study provides a computational estimate of the identity and number of targets needed in combination to target cancers selectively and precisely.
    DOI:  https://doi.org/10.1038/s41467-022-29154-2
  35. J Thorac Oncol. 2022 Apr;pii: S1556-0864(21)02432-1. [Epub ahead of print]17(4): e49-e50
    Genomically Metastatic, but Surgically Curable?
    Taichiro Goto.
      
    DOI:  https://doi.org/10.1016/j.jtho.2021.07.037
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