bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021‒12‒05
twenty-one papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology
  1. Distinct contributions of partial and full EMT to breast cancer malignancy.
  2. Targeting Treg-expressed STAT3 enhances NK-mediated surveillance of metastasis and improves therapeutic response in pancreatic adenocarcinoma.
  3. Pharmacological reduction of mitochondrial iron triggers a non-canonical BAX/BAK dependent cell death.
  4. Mutant-IDH inhibits Interferon-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma.
  5. Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition.
  6. Mesenchymal type neuroblastoma cells escape ALK inhibitors.
  7. Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids.
  8. A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers.
  9. Multi-omics analysis of spatially distinct stromal cells reveals tumor-induced O-glycosylation of the CDK4-pRB axis in fibroblasts at the invasive tumor edge.
  10. Single cell-derived spheroids capture the self-renewing subpopulations of metastatic ovarian cancer.
  11. E-Cadherin: Context-Dependent Functions of a Quintessential Epithelial Marker in Metastasis.
  12. RSPO2/RANKL-LGR4 signaling regulates osteoclastic pre-metastatic niche formation and bone metastasis.
  13. Hypoxia as a driver of resistance to immunotherapy.
  14. Redox-sensitive cyclophilin A elicits chemoresistance through realigning cellular oxidative status in colorectal cancer.
  15. The keratin 17/YAP/IL6 axis contributes to E-cadherin loss and aggressiveness of diffuse gastric cancer.
  16. Elimination of fluorescent protein immunogenicity permits modeling of metastasis in immune-competent settings.
  17. The Antibiotic Drug Trimethoprim Suppresses Tumor Growth and Metastasis via Targeting Snail.
  18. Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.
  19. Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer.
  20. GTF2E2 is a novel biomarker for recurrence after surgery and promotes progression of esophageal squamous cell carcinoma via miR-139-5p/GTF2E2/FUS axis.
  21. Network Analysis Identifies Regulators of Basal-Like Breast Cancer Reprogramming and Endocrine Therapy Vulnerability.
  1. Dev Cell. 2021 Nov 23. pii: S1534-5807(21)00891-1. [Epub ahead of print]
    Distinct contributions of partial and full EMT to breast cancer malignancy.
    Fabiana Lüönd, Nami Sugiyama, Ruben Bill, Laura Bornes, Carolina Hager, Fengyuan Tang, Natascha Santacroce, Christian Beisel, Robert Ivanek, Thomas Bürglin, Stefanie Tiede, Jacco van Rheenen, Gerhard Christofori.
      Epithelial-mesenchymal transition (EMT) is a transient, reversible process of cell de-differentiation where cancer cells transit between various stages of an EMT continuum, including epithelial, partial EMT, and mesenchymal cell states. We have employed Tamoxifen-inducible dual recombinase lineage tracing systems combined with live imaging and 5-cell RNA sequencing to track cancer cells undergoing partial or full EMT in the MMTV-PyMT mouse model of metastatic breast cancer. In primary tumors, cancer cells infrequently undergo EMT and mostly transition between epithelial and partial EMT states but rarely reach full EMT. Cells undergoing partial EMT contribute to lung metastasis and chemoresistance, whereas full EMT cells mostly retain a mesenchymal phenotype and fail to colonize the lungs. However, full EMT cancer cells are enriched in recurrent tumors upon chemotherapy. Hence, cancer cells in various stages of the EMT continuum differentially contribute to hallmarks of breast cancer malignancy, such as tumor invasion, metastasis, and chemoresistance.
    Keywords:  EMT; EMT continuum; breast cancer; collective cell migration; dual recombinase; lineage tracing; metastasis; mouse models; therapy resistance
    DOI:  https://doi.org/10.1016/j.devcel.2021.11.006
  2. Clin Cancer Res. 2021 Dec 03. pii: clincanres.2767.2021. [Epub ahead of print]
    Targeting Treg-expressed STAT3 enhances NK-mediated surveillance of metastasis and improves therapeutic response in pancreatic adenocarcinoma.
    Miles Piper, Benjamin Van Court, Adam Mueller, Shuichi Watanabe, Thomas Bickett, Shilpa Bhatia, Laurel B Darragh, Maxwell Mayeda, Diemmy Nguyen, Jacob Gadwa, Michael Knitz, Sophia Corbo, Rustain Morgan, Jung-Jae Lee, Alexander Dent, Karyn Goodman, Wells Messersmith, Richard Schulick, Marco Del Chiaro, Yuwen Zhu, Ross M Kedl, Laurel Lenz, Sana D Karam.
      PURPOSE: Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden.METHODS: Patient PDAC tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following RT. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations.
    RESULTS: We demonstrate that although RT increases the infiltration and activation of DCs, it also increases the infiltration of Tregs while failing to recruit NK and CD8 T cells in PDAC patient samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to RT, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 ASO and RT invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + RT treatment is dependent on NK and DC subsets.
    CONCLUSIONS: Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment and identify NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-2767
  3. Cancer Discov. 2021 Dec 03. pii: candisc.0522.2021. [Epub ahead of print]
    Pharmacological reduction of mitochondrial iron triggers a non-canonical BAX/BAK dependent cell death.
    Sylvain Garciaz, Andrew A Guirguis, Sebastian Muller, Fiona C Brown, Yih-Chih Chan, Ali Motazedian, Caitlin L Rowe, James A Kuzich, Kah Lok Chan, Kevin Tran, Lorey Smith, Laura MacPherson, Brian Liddicoat, Enid Y N Lam, Tatiana Caneque, Marian L Burr, Veronique Litalien, Giovanna Pomilio, Mathilde Poplineau, Estelle Duprez, Sarah-Jane Dawson, Georg Ramm, Andrew G Cox, Kristin K Brown, David C S Huang, Andrew H Wei, Kate McArthur, Raphael Rodriguez, Mark A Dawson.
      Cancer cell metabolism is increasingly recognised as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small molecule ironomycin (AM5) reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent non-redundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0522
  4. Cancer Discov. 2021 Nov 30. pii: candisc.1077.2021. [Epub ahead of print]
    Mutant-IDH inhibits Interferon-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma.
    Meng-Ju Wu, Lei Shi, Juan Dubrot, Joshua Merritt, Vindhya Vijay, Ting-Yu Wei, Emily Kessler, Kira E Olander, Ramzi Adil, Amaya Pankaj, Krishna Seshu Tummala, Vajira Weeresekara, Yuanli Zhen, Qibiao Wu, Meiqi Luo, William Shen, Maria Garcia-Beccaria, Mirian Fernandez-Vaquero, Christine Hudson, Sebastien Ronseaux, Yi Sun, Rodrigo Saad-Berreta, Russell W Jenkins, Tong Wang, Mathias Heikenwalder, Cristina R Ferrone, Lipika Goyal, Brandon Nicolay, Vikram Deshpande, Rahul M Kohli, Hongwu Zheng, Robert T Manguso, Nabeel Bardeesy.
      Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple a-ketoglutarate-dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate-mediated mechanisms - suppression of CD8+ T cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacological mIDH1 inhibition stimulates CD8+ T cell recruitment and IFN-y expression and promotes TET2-dependent induction of IFN-y response genes in tumor cells. CD8+ T cell depletion or tumor cell-specific ablation of TET2 or Interferon-gamma receptor 1 causes treatment resistance. Whereas immune checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFN-y-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for harnessing these inhibitors therapeutically.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-1077
  5. Oncogene. 2021 Nov 29.
    Prostate tumor-induced stromal reprogramming generates Tenascin C that promotes prostate cancer metastasis through YAP/TAZ inhibition.
    Yu-Chen Lee, Song-Chang Lin, Guoyu Yu, Ming Zhu, Jian H Song, Keith Rivera, Darryl J Pappin, Christopher J Logothetis, Theocharis Panaretakis, Guocan Wang, Li-Yuan Yu-Lee, Sue-Hwa Lin.
      Metastatic prostate cancer (PCa) in bone induces bone-forming lesions that enhance PCa progression. How tumor-induced bone formation enhances PCa progression is not known. We have previously shown that PCa-induced bone originates from endothelial cells (ECs) that have undergone endothelial-to-osteoblast (EC-to-OSB) transition by tumor-secreted bone morphogenetic protein 4 (BMP4). Here, we show that EC-to-OSB transition leads to changes in the tumor microenvironment that increases the metastatic potential of PCa cells. We found that conditioned medium (CM) from EC-OSB hybrid cells increases the migration, invasion, and survival of PC3-mm2 and C4-2B4 PCa cells. Quantitative mass spectrometry (Isobaric Tags for Relative and Absolute Quantitation) identified Tenascin C (TNC) as one of the major proteins secreted from EC-OSB hybrid cells. TNC expression in tumor-induced OSBs was confirmed by immunohistochemistry of MDA PCa-118b xenograft and human bone metastasis specimens. Mechanistically, BMP4 increases TNC expression in EC-OSB cells through the Smad1-Notch/Hey1 pathway. How TNC promotes PCa metastasis was next interrogated by in vitro and in vivo studies. In vitro studies showed that a TNC-neutralizing antibody inhibits EC-OSB-CM-mediated PCa cell migration and survival. TNC knockdown decreased, while the addition of recombinant TNC or TNC overexpression increased migration and anchorage-independent growth of PC3 or C4-2b cells. When injected orthotopically, PC3-mm2-shTNC clones decreased metastasis to bone, while C4-2b-TNC-overexpressing cells increased metastasis to lymph nodes. TNC enhances PCa cell migration through α5β1 integrin-mediated YAP/TAZ inhibition. These studies elucidate that tumor-induced stromal reprogramming generates TNC that enhances PCa metastasis and suggest that TNC may be a target for PCa therapy.
    DOI:  https://doi.org/10.1038/s41388-021-02131-7
  6. Cancer Res. 2021 Dec 01. pii: canres.1621.2021. [Epub ahead of print]
    Mesenchymal type neuroblastoma cells escape ALK inhibitors.
    Ellen M Westerhout, Mohamed Hamdi, Peter Stroeken, Natalia E Nowakowska, Arjan Lakeman, Jennemiek van Arkel, Nancy E Hasselt, Boris Bleijlevens, Nurdan Akogul, Franciska Haneveld, Alvin Chan, Peter van Sluis, Danny Zwijnenburg, Richard Volckmann, Carel Jm van Noesel, Igor Adameyko, Tim van Groningen, Jan Koster, Linda J Valentijn, Johan van Nes, Rogier Versteeg.
      Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating ALK mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1621
  7. Nat Commun. 2021 Dec 01. 12(1): 7014
    Comprehensive targeting of resistance to inhibition of RTK signaling pathways by using glucocorticoids.
    Ke Gong, Gao Guo, Nicole A Beckley, Xiaoyao Yang, Yue Zhang, David E Gerber, John D Minna, Sandeep Burma, Dawen Zhao, Esra A Akbay, Amyn A Habib.
      Inhibition of RTK pathways in cancer triggers an adaptive response that promotes therapeutic resistance. Because the adaptive response is multifaceted, the optimal approach to blunting it remains undetermined. TNF upregulation is a biologically significant response to EGFR inhibition in NSCLC. Here, we compared a specific TNF inhibitor (etanercept) to thalidomide and prednisone, two drugs that block TNF and also other inflammatory pathways. Prednisone is significantly more effective in suppressing EGFR inhibition-induced inflammatory signals. Remarkably, prednisone induces a shutdown of bypass RTK signaling and inhibits key resistance signals such as STAT3, YAP and TNF-NF-κB. Combined with EGFR inhibition, prednisone is significantly superior to etanercept or thalidomide in durably suppressing tumor growth in multiple mouse models, indicating that a broad suppression of adaptive signals is more effective than blocking a single component. We identify prednisone as a drug that can effectively inhibit adaptive resistance with acceptable toxicity in NSCLC and other cancers.
    DOI:  https://doi.org/10.1038/s41467-021-27276-7
  8. Nat Cell Biol. 2021 Dec 02.
    A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers.
    A Fatehullah, Y Terakado, S Sagiraju, T L Tan, T Sheng, S H Tan, K Murakami, Y Swathi, N Ang, R Rajarethinam, T Ming, P Tan, B Lee, N Barker.
      Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5+ populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically relevant mechanistic insights into cancer progression and as preclinical models for evaluating therapeutic targets.
    DOI:  https://doi.org/10.1038/s41556-021-00793-9
  9. Cancer Res. 2021 Dec 01. pii: canres.1705.2021. [Epub ahead of print]
    Multi-omics analysis of spatially distinct stromal cells reveals tumor-induced O-glycosylation of the CDK4-pRB axis in fibroblasts at the invasive tumor edge.
    Gina Bouchard, Fernando J Garcia-Marques, Loukia G Karacosta, Weiruo Zhang, Abel Bermudez, Nicholas M Riley, Sushama Varma, Lindsey C Mehl, Jalen A Benson, Joseph B Shrager, Carolyn R Bertozzi, Sharon J Pitteri, Amato J Giaccia, Sylvia K Plevritis.
      The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that crosstalk between tumor and stromal cells within the tumor microenvironment (TME) results in activation of key biological pathways depending on their position in the tumor (edge vs core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts (TCF) from the tumor core, established from human lung adenocarcinomas. A multi-omics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize crosstalk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential post-translational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 and phosphorylated retinoblastoma protein (CDK4-pRB) axis in the stroma and indirectly modulates pro-invasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor-stroma crosstalk and a potential avenue to improve the anti-cancer efficacy of CDK4 inhibitors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1705
  10. Cell Death Differ. 2021 Nov 29.
    Single cell-derived spheroids capture the self-renewing subpopulations of metastatic ovarian cancer.
    Tania Velletri, Carlo Emanuele Villa, Domenica Cilli, Bianca Barzaghi, Pietro Lo Riso, Michela Lupia, Raffaele Luongo, Alejandro López-Tobón, Marco De Simone, Raoul J P Bonnal, Luca Marelli, Stefano Piccolo, Nicoletta Colombo, Massimiliano Pagani, Ugo Cavallaro, Saverio Minucci, Giuseppe Testa.
      High Grade Serous Ovarian cancer (HGSOC) is a major unmet need in oncology, due to its precocious dissemination and the lack of meaningful human models for the investigation of disease pathogenesis in a patient-specific manner. To overcome this roadblock, we present a new method to isolate and grow single cells directly from patients' metastatic ascites, establishing the conditions for propagating them as 3D cultures that we refer to as single cell-derived metastatic ovarian cancer spheroids (sMOCS). By single cell RNA sequencing (scRNAseq) we define the cellular composition of metastatic ascites and trace its propagation in 2D and 3D culture paradigms, finding that sMOCS retain and amplify key subpopulations from the original patients' samples and recapitulate features of the original metastasis that do not emerge from classical 2D culture, including retention of individual patients' specificities. By enabling the enrichment of uniquely informative cell subpopulations from HGSOC metastasis and the clonal interrogation of their diversity at the functional and molecular level, this method provides a powerful instrument for precision oncology in ovarian cancer.
    DOI:  https://doi.org/10.1038/s41418-021-00878-w
  11. Cancer Res. 2021 Dec 01. 81(23): 5800-5802
    E-Cadherin: Context-Dependent Functions of a Quintessential Epithelial Marker in Metastasis.
    Cao Fang, Yibin Kang.
      Loss of E-cadherin expression has been well known as a hallmark of epithelial-mesenchymal transition (EMT), which is linked to increased risk of cancer metastasis. However, it was less clear whether E-cadherin and its downstream signaling pathways are functionally involved in driving EMT and the prometastatic phenotype. A study by Onder and colleagues in 2008 discovered that E-cadherin loss not only helps tumor cells detach from each other by breaking down cell-cell junctions but also elicits intracellular signaling events to confer a mesenchymal cell state and metastatic phenotype. This study established E-cadherin as an important global regulator, rather than just a marker, of EMT. The discovery inspired further investigation in the following decade that significantly deepened our understanding of E-cadherin and its diverse functions and more broadly of cellular plasticity in different stages and contexts of cancer metastasis.See related article by Onder and colleagues, Cancer Res 2008;68:3645-54.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3302
  12. J Clin Invest. 2021 Nov 30. pii: e144579. [Epub ahead of print]
    RSPO2/RANKL-LGR4 signaling regulates osteoclastic pre-metastatic niche formation and bone metastasis.
    Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo.
      Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate pre-metastatic niche and bone tropism is largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a pre-metastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interacting with their receptor LGR4, promoted osteoclastic pre-metastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating WNT inhibitor DKK1 through Gαq and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppressing its receptor low-density lipoprotein-related receptors 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibiting canonical WNT signaling. In clinical samples, RSPO2, LGR4 and DKK1 expression showed positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of pre-metastatic niche for BCa bone metastasis, indicate RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.
    Keywords:  Bone Biology; Bone disease; Breast cancer; Cell Biology; Signal transduction
    DOI:  https://doi.org/10.1172/JCI144579
  13. Drug Resist Updat. 2021 Nov 18. pii: S1368-7646(21)00045-5. [Epub ahead of print] 100787
    Hypoxia as a driver of resistance to immunotherapy.
    Joanna Kopecka, Iris C Salaroglio, Elizabeth Perez-Ruiz, Ana Bela Sarmento-Ribeiro, Simona Saponara, Javier De Las Rivas, Chiara Riganti.
      Hypoxia, a hallmark of solid tumors, determines the selection of invasive and aggressive malignant clones displaying resistance to radiotherapy, conventional chemotherapy or targeted therapy. The recent introduction of immunotherapy, based on immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cells, has markedly transformed the prognosis in some tumors but also revealed the existence of intrinsic or acquired drug resistance. In the current review we highlight hypoxia as a culprit of immunotherapy failure. Indeed, multiple metabolic cross talks between tumor and stromal cells determine the prevalence of immunosuppressive populations within the hypoxic tumor microenvironment and confer upon tumor cells resistance to ICPIs and CAR T-cells. Notably, hypoxia-triggered angiogenesis causes immunosuppression, adding another piece to the puzzle of hypoxia-induced immunoresistance. If these factors concurrently contribute to the resistance to immunotherapy, they also unveil an unexpected Achille's heel of hypoxic tumors, providing the basis for innovative combination therapies that may rescue the efficacy of ICPIs and CAR T-cells. Although these treatments reveal both a bright side and a dark side in terms of efficacy and safety in clinical trials, they represent the future solution to enhance the efficacy of immunotherapy against hypoxic and therapy-resistant solid tumors.
    Keywords:  CAR T-cells; Drug resistance; Immune checkpoint inhibitors; Tumor hypoxia
    DOI:  https://doi.org/10.1016/j.drup.2021.100787
  14. Cell Rep. 2021 Nov 30. pii: S2211-1247(21)01555-2. [Epub ahead of print]37(9): 110069
    Redox-sensitive cyclophilin A elicits chemoresistance through realigning cellular oxidative status in colorectal cancer.
    Liyuan Peng, Jingwen Jiang, Hai-Ning Chen, Li Zhou, Zhao Huang, Siyuan Qin, Ping Jin, Maochao Luo, Bowen Li, Jiayan Shi, Na Xie, Lih-Wen Deng, Yih-Cherng Liou, Edouard C Nice, Canhua Huang, Yuquan Wei.
      Cancer cells utilize rapidly elevated cellular antioxidant programs to accommodate chemotherapy-induced oxidative stress; however, the underlying mechanism remains largely unexplored. Here we screen redox-sensitive effectors as potential therapeutic targets for colorectal cancer (CRC) treatment and find that cyclophilin A (CypA) is a compelling candidate. Our results show that CypA forms an intramolecular disulfide bond between Cys115 and Cys161 upon oxidative stress and the oxidized cysteines in CypA are recycled to a reduced state by peroxiredoxin-2 (PRDX2). Furthermore, CypA reduces cellular reactive oxygen species levels and increases CRC cell survival under insults of H2O2 and chemotherapeutics through a CypA-PRDX2-mediated antioxidant apparatus. Notably, CypA is upregulated in chemoresistant CRC samples, which predicts poor prognosis. Moreover, targeting CypA by cyclosporine A exhibits promising efficacy against chemoresistant CRC when combined with chemotherapeutics. Collectively, our findings highlight CypA as a component of cellular noncanonical antioxidant defense and as a potential druggable therapeutic target to ameliorate CRC chemoresistance.
    Keywords:  CRC; CypA; PRDX2; ROS; antioxidant system; colorectal cancer; disulfide bond; drug resistance; oxidative stress; reactive oxygen species; redox modification; redox signaling
    DOI:  https://doi.org/10.1016/j.celrep.2021.110069
  15. Oncogene. 2021 Nov 29.
    The keratin 17/YAP/IL6 axis contributes to E-cadherin loss and aggressiveness of diffuse gastric cancer.
    Mengjie Li, Xianping Rao, Yun Cui, Lu Zhang, Xiang Li, Boya Wang, Yijun Zheng, Lisong Teng, Tianhua Zhou, Wei Zhuo.
      DGC is a particular aggressive malignancy with poor prognosis. Recent omics studies characterized DGC with CDH1/E-cadherin loss and EMT-signatures. However, the underlying mechanisms for maintaining the aggressive behavior and molecular features of DGC remain unclear. Here, we find that intermediate filaments KRT17 is significantly lower in DGC tissues than that in intestinal gastric cancer tissues and associated with poor prognosis of DGC. We demonstrate that downregulation of KRT17 induces E-cadherin loss, EMT changes, and metastasis behaviors of GC cells. Mechanistically, the loss of intermediate filaments KRT17 induces reorganization of cytoskeleton, further activates YAP signaling, and increases IL6 expression, which contributes to the enhanced metastasis ability of GC cells. Together, these results indicate that KRT17/YAP/IL6 axis contributes to maintaining E-cadherin loss, EMT feature, and metastasis of DGC, providing a new insight into the role of aberrant intermediate filaments in DGC malignancy.
    DOI:  https://doi.org/10.1038/s41388-021-02119-3
  16. Cancer Cell. 2021 Nov 12. pii: S1535-6108(21)00604-8. [Epub ahead of print]
    Elimination of fluorescent protein immunogenicity permits modeling of metastasis in immune-competent settings.
    Candice A Grzelak, Erica T Goddard, Emma E Lederer, Kamya Rajaram, Jinxiang Dai, Ryann E Shor, Andrea R Lim, Jeanna Kim, Slobodan Beronja, Alister P W Funnell, Cyrus M Ghajar.
      
    DOI:  https://doi.org/10.1016/j.ccell.2021.11.004
  17. Br J Pharmacol. 2021 Dec 02.
    The Antibiotic Drug Trimethoprim Suppresses Tumor Growth and Metastasis via Targeting Snail.
    Bo-Xue Ren, Yang Li, Hong-Mei Li, Tao Lu, Zhao-Qiu Wu, Rong Fu.
      BACKGROUND AND PURPOSE: The zinc finger transcription factor Snail is aberrantly activated in many human cancers and strongly associated with poor prognosis. As a transcription factor, Snail has been traditionally considered an "undruggable" target. Here, we identified a potent small molecule inhibitor of Snail, namely trimethoprim, and investigated its potential antitumor effects and the underlying mechanisms.EXPERIMENTAL APPROACH: The inhibitory action of trimethoprim on Snail protein and the related molecular mechanisms were revealed by molecular docking, biolayer interferometry, immunoblotting, immunoprecipitation, qRT-PCR, pull-down, and cycloheximide pulse-chase assays. The anti-proliferative and anti-metastatic effects of trimethoprim via targeting Snail were tested in multiple cell-based assays and animal models.
    KEY RESULTS: This study identified trimethoprim, an antimicrobial drug, as a potent anti-tumor agent via targeting Snail. Molecular modeling analysis predicted that trimethoprim directly binds to the arginine-174 pocket of Snail protein. We further discovered that trimethoprim strongly interrupts the interaction of Snail with CREB-binding protein (CBP)/p300, which consequently suppresses Snail acetylation and promotes Snail degradation through ubiquitin-proteasome pathway. Furthermore, trimethoprim sufficiently inhibited the proliferation, epithelial-mesenchymal transition (EMT), and migration of cancer cells in vitro via specifically targeting Snail. More importantly, trimethoprim effectively reduced Snail-driven tumor growth and metastasis to vital organs such as lung, bone, and liver.
    CONCLUSIONS AND IMPLICATIONS: These findings indicate, for the first time, that trimethoprim suppresses tumor growth and metastasis via targeting Snail. This study provides insights for a better understanding of the anticancer effects of trimethoprim and offers a potential anti-cancer therapeutic agent for clinical treatment.
    Keywords:  Snail; drug repurposing; epithelial-mesenchymal transition; trimethoprim; tumor growth and metastasis
    DOI:  https://doi.org/10.1111/bph.15763
  18. Nat Commun. 2021 Nov 29. 12(1): 6960
    Subclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single-cell transcriptomics.
    Stephan M Tirier, Jan-Philipp Mallm, Simon Steiger, Alexandra M Poos, Mohamed H S Awwad, Nicola Giesen, Nicola Casiraghi, Hana Susak, Katharina Bauer, Anja Baumann, Lukas John, Anja Seckinger, Dirk Hose, Carsten Müller-Tidow, Hartmut Goldschmidt, Oliver Stegle, Michael Hundemer, Niels Weinhold, Marc S Raab, Karsten Rippe.
      Virtually all patients with multiple myeloma become unresponsive to treatment over time. Relapsed/refractory multiple myeloma (RRMM) is accompanied by the clonal evolution of myeloma cells with heterogeneous genomic aberrations and profound changes of the bone marrow microenvironment (BME). However, the molecular mechanisms that drive drug resistance remain elusive. Here, we analyze the heterogeneous tumor cell population and its complex interaction network with the BME of 20 RRMM patients by single cell RNA-sequencing before/after treatment. Subclones with chromosome 1q-gain express a specific transcriptomic signature and frequently expand during treatment. Furthermore, RRMM cells shape an immune suppressive BME by upregulation of inflammatory cytokines and close interaction with the myeloid compartment. It is characterized by the accumulation of PD1+ γδ T-cells and tumor-associated macrophages as well as the depletion of hematopoietic progenitors. Thus, our study resolves transcriptional features of subclones in RRMM and mechanisms of microenvironmental reprogramming with implications for clinical decision-making.
    DOI:  https://doi.org/10.1038/s41467-021-26951-z
  19. Nat Commun. 2021 Dec 01. 12(1): 7006
    Nicotine-mediated OTUD3 downregulation inhibits VEGF-C mRNA decay to promote lymphatic metastasis of human esophageal cancer.
    Meng Wang, Yue Li, Yunyun Xiao, Muwen Yang, Jinxin Chen, Yunting Jian, Xin Chen, Dongni Shi, Xiangfu Chen, Ying Ouyang, Lingzhi Kong, Xinjian Huang, Jiewen Bai, Chuyong Lin, Libing Song.
      Nicotine addiction and the occurrence of lymph node spread are two major significant factors associated with esophageal cancer's poor prognosis; however, nicotine's role in inducing lymphatic metastasis of esophageal cancer remains unclear. Here we show that OTU domain-containing protein 3 (OTUD3) is downregulated by nicotine and correlates with poor prognosis in heavy-smoking esophageal cancer patients. OTUD3 directly interacts with ZFP36 ring finger protein (ZFP36) and stabilizes it by inhibiting FBXW7-mediated K48-linked polyubiquitination. ZFP36 binds with the VEGF-C 3-'UTR and recruits the RNA degrading complex to induce its rapid mRNA decay. Downregulation of OTUD3 and ZFP36 is essential for nicotine-induced VEGF-C production and lymphatic metastasis in esophageal cancer. This study establishes that the OTUD3/ZFP36/VEGF-C axis plays a vital role in nicotine addiction-induced lymphatic metastasis, suggesting that OTUD3 may serve as a prognostic marker, and induction of the VEGF-C mRNA decay might be a potential therapeutic strategy against human esophageal cancer.
    DOI:  https://doi.org/10.1038/s41467-021-27348-8
  20. Oncogene. 2021 Dec 02.
    GTF2E2 is a novel biomarker for recurrence after surgery and promotes progression of esophageal squamous cell carcinoma via miR-139-5p/GTF2E2/FUS axis.
    Yujie Zhang, Yuxin Zhang, Bo Ai, Juejun Gong, Yichen Li, Shiying Yu, Xiuyu Cai, Li Zhang.
      Esophageal squamous cell carcinoma (ESCC) is one of the most lethal gastrointestinal malignancies with high mortality. Recurrence develops within only a few years after curative resection and perioperative adjuvant therapy in 30-50% of these patients. Therefore, it is essential to identify postoperative recurrence biomarkers to facilitate selecting the following surveillance and therapeutic strategies. The general transcription factor IIE subunit beta (GTF2E2) is crucial for physiological and pathological functions, but its roles in the aggression and recurrence of ESCC remain ambiguous. In this study, we found that GTF2E2 was highly expressed in ESCC samples, and elevated GTF2E2 expression predicted early recurrence after surgery for ESCC patients. High expression of GTF2E2 associated with more aggressive clinic features and poor prognosis. GTF2E2 promoted the proliferation and mobility of ESCC cells in vitro and in vivo. We further revealed that miR-139-5p repressed GTF2E2 expression by downregulating its mRNA through binding with Argonaute 2 (Ago2). Rescue assays suggested that miR-139-5p affected GTF2E2-mediated ESCC progression. Moreover, GTF2E2 positively interacted with FUS promoter and regulated FUS expression, and the phenotype changes caused by GTF2E2 manipulation were recovered by rescuing FUS expression in ESCC cells. Additionally, we demonstrated that GTF2E2 promotes ESCC cells progression via activation of the AKT/ERK/mTOR pathway. In conclusion, GTF2E2 may serve as a novel biomarker for recurrence after surgery and a potential therapeutic target for ESCC patients, and it promotes ESCC progression via miR-139-5p/GTF2E2/FUS axis.
    DOI:  https://doi.org/10.1038/s41388-021-02122-8
  21. Cancer Res. 2021 Nov 29.
    Network Analysis Identifies Regulators of Basal-Like Breast Cancer Reprogramming and Endocrine Therapy Vulnerability.
    Sea R Choi, Chae Young Hwang, Jonghoon Lee, Kwang-Hyun Cho.
      Basal-like breast cancer is the most aggressive breast cancer subtype with the worst prognosis. Despite its high recurrence rate, chemotherapy is the only treatment for basal-like breast cancer, which lacks expression of hormone receptors. In contrast, luminal A tumors express ERα and can undergo endocrine therapy for treatment. Previous studies have tried to develop effective treatments for basal-like patients using various therapeutics but failed due to the complex and dynamic nature of the disease. In this study, we performed a transcriptomic analysis of patients with breast cancer to construct a simplified but essential molecular regulatory network model. Network control analysis identified potential targets and elucidated the underlying mechanisms of reprogramming basal-like cancer cells into luminal A cells. Inhibition of BCL11A and HDAC1/2 effectively drove basal-like cells to transition to luminal A cells and increased ERα expression, leading to increased tamoxifen sensitivity. High expression of BCL11A and HDAC1/2 correlated with poor prognosis in patients with breast cancer. These findings identify mechanisms regulating breast cancer phenotypes and suggest the potential to reprogram basal-like breast cancer cells to enhance their targetability. SIGNIFICANCE: A network model enables investigation of mechanisms regulating the basal-to-luminal transition in breast cancer, identifying BCL11A and HDAC1/2 as optimal targets that can induce basal-like breast cancer reprogramming and endocrine therapy sensitivity.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-0621
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