bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–06–20
thirty-one papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma.
  2. Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs.
  3. The HSF1/miR-135b-5p axis induces protective autophagy to promote oxaliplatin resistance through the MUL1/ULK1 pathway in colorectal cancer.
  4. E2A modulates stemness, metastasis, and therapeutic resistance of breast cancer.
  5. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
  6. Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair.
  7. ENO1 promotes lung cancer metastasis via HGFR and WNT signaling-driven epithelial-mesenchymal transition.
  8. Single-Cell Lineage Tracing of Metastasis Uncovers an EMT Continuum.
  9. Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance.
  10. LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit.
  11. Cancer cell adaptability: turning ribonucleoprotein granules into targets.
  12. STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma.
  13. IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment.
  14. MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly.
  15. Innate immune cells in the tumor microenvironment.
  16. IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells.
  17. BRN2 is a non-canonical melanoma tumor-suppressor.
  18. Metabolic alterations mediated by STAT3 promotes drug persistence in CML.
  19. Immunological barriers to immunotherapy in primary and metastatic breast cancer.
  20. IL-6 regulates autophagy and chemotherapy resistance by promoting BECN1 phosphorylation.
  21. Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.
  22. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance.
  23. When dormancy fuels tumour relapse.
  24. Eradicating micrometastases with immune checkpoint blockade: Strike while the iron is hot.
  25. Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells.
  26. Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate.
  27. Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer.
  28. Preventing breast cancer recurrence.
  29. Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity.
  30. Complementary role of circulating tumor DNA assessment and tissue genomic profiling in metastatic renal cell carcinoma.
  31. A systematic CRISPR screen reveals an IL-20/IL20RA-mediated immune crosstalk to prevent the ovarian cancer metastasis.
  1. Cancer Cell. 2021 Jun 07. pii: S1535-6108(21)00281-6. [Epub ahead of print]
    Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma.
    Oskar Marin-Bejar, Aljosja Rogiers, Michael Dewaele, Julia Femel, Panagiotis Karras, Joanna Pozniak, Greet Bervoets, Nina Van Raemdonck, Dennis Pedri, Toon Swings, Jonas Demeulemeester, Sara Vander Borght, Stefan Lehnert, Francesca Bosisio, Joost J van den Oord, Isabelle Vanden Bempt, Diether Lambrechts, Thierry Voet, Oliver Bechter, Helen Rizos, Mitchell P Levesque, Eleonora Leucci, Amanda W Lund, Florian Rambow, Jean-Christophe Marine.
      Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to mitogen-activated protein kinase therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a glial cell line-derived neurotrophic factor-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to extracellular signal-regulated kinase inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.
    Keywords:  FAK signaling; cutaneous melanoma; minimal residual disease; neural crest stem cells; nongenetic reprogramming; patient-derived tumor xenografts; single-cell sequencing; therapy resistance
    DOI:  https://doi.org/10.1016/j.ccell.2021.05.015
  2. Nat Cancer. 2020 Jun;1(6): 603-619
    Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs.
    Jun Gui, Farima Zahedi, Angelica Ortiz, Christina Cho, Kanstantsin V Katlinski, Kevin Alicea-Torres, Jinyang Li, Leslie Todd, Hongru Zhang, Daniel P Beiting, Cindy Sander, John M Kirkwood, Bryan E Snow, Andrew C Wakeham, Tak W Mak, J Alan Diehl, Constantinos Koumenis, Sandra W Ryeom, Ben Z Stanger, Ellen Puré, Dmitry I Gabrilovich, Serge Y Fuchs.
      Primary tumor-derived factors (TDFs) act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that TDFs-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and subsequent pulmonary metastases. Activation of p38α led to inactivation of type I interferon signaling and stimulation of expression of fibroblast activation protein (FAP). FAP played a key role in remodeling of the extracellular matrix as well as inducing the expression of chemokines that enable lung infiltration by neutrophils. Increased activity of p38 in normal cells was associated with metastatic disease and poor prognosis in human melanoma patients whereas inactivation of p38 suppressed lung metastases. We discuss the p38α-driven mechanisms stimulating the metastatic processes and potential use of p38 inhibitors in adjuvant therapy of metastatic cancers.
    Keywords:  IFNAR1; adjuvant therapy; fibroblast activation protein; interferon; lung metastasis; melanoma; metastatic cancer; p38 inhibitor; p38 kinase; pancreatic ductal adenocarcinoma; pre-metastatic niche; tumor-derived factors
    DOI:  https://doi.org/10.1038/s43018-020-0064-0
  3. Oncogene. 2021 Jun 17.
    The HSF1/miR-135b-5p axis induces protective autophagy to promote oxaliplatin resistance through the MUL1/ULK1 pathway in colorectal cancer.
    Huiya Wang, Xia Wang, Haiyang Zhang, Ting Deng, Rui Liu, Ying Liu, Hongli Li, Ming Bai, Tao Ning, Junyi Wang, Shaohua Ge, Yi Ba.
      Oxaliplatin (oxa) is widely used in the treatment of colorectal cancer (CRC), but the development of oxaliplatin resistance is a major obstacle to the therapeutic efficacy in patients. MicroRNAs (miRNAs), endogenous noncoding RNAs measuring between 22 and 24 nucleotides, have been shown to be involved in the development of CRC drug resistance. However, the mechanism by which differentially expressed miRNAs induce chemotherapy resistance in CRC has not been fully elucidated to date. Here, we showed the differentially expressed miRNAs in oxaliplatin-sensitive and oxaliplatin-resistant CRC cells through miRNA microarray technology and found that miR-135b-5p was significantly increased in oxaliplatin-resistant cells. And miR-135b-5p was increased in the serum of colorectal cancer patients. More importantly, the miR-135b-5p level in the serum of oxaliplatin-resistant patients was further increased compared to that of oxaliplatin-sensitive patients. Recent studies have shown that protective autophagy is an important mechanism that promotes drug resistance in tumors. The potential role of miR-135b-5p in inducing protective autophagy and promoting oxaliplatin resistance was evaluated in two stable oxaliplatin-resistant CRC cell lines and their parental cells. We further identified MUL1 as a direct downstream target of miR-135b-5p and showed that MUL1 could degrade the key molecule of autophagy, ULK1, through ubiquitination. Mouse xenograft models were adopted to evaluate the correlation between miR-135b-5p and oxaliplatin-induced autophagy in vivo. Furthermore, we also investigated the regulatory factors for the upregulation of miR-135b-5p in CRC cells under oxaliplatin chemotoxicity. These results indicated that miR-135b-5p upregulation in colorectal cancer could induce protective autophagy through the MUL1/ULK1 signaling pathway and promote oxaliplatin resistance. Targeting miR-135b-5p may provide a new treatment strategy for reversing oxaliplatin resistance in CRC.
    DOI:  https://doi.org/10.1038/s41388-021-01898-z
  4. Cancer Res. 2021 Jun 18. pii: canres.2685.2020. [Epub ahead of print]
    E2A modulates stemness, metastasis, and therapeutic resistance of breast cancer.
    Amparo Cano, Celia López-Menéndez, Alberto Vázquez-Naharro, Vanesa Santos, Pierre Dubus, Patricia G Santamaría, Ángel Martínez-Ramírez, Francisco Portillo, Gema Moreno-Bueno, Marisa M Faraldo.
      Cancer stem cells (CSC) are considered responsible for tumor initiation, therapeutic resistance, and metastasis. A comprehensive knowledge of the mechanisms governing the acquisition and maintenance of cancer stemness is crucial for the development of new therapeutic approaches in oncology. E2A basic helix-loop-helix (bHLH) transcription factors are associated with epithelial-mesenchymal transition (EMT) and tumor progression, but knowledge of their functional contributions to cancer biology is still limited. Using a combination of in vivo and in vitro analyses in a novel PyMT-E2A conditional knockout mouse model and derived primary tumor cell lines, we report here an essential role of E2A in stemness, metastasis, and therapeutic resistance in breast cancer. Targeted deletion of E2A in the mammary gland impaired tumor initiating ability and dedifferentiation potential and severely compromised metastatic competence of PyMT-driven mammary tumors. Mechanistic studies in PyMT-derived cell lines indicated that E2A actions are mediated by the upregulation of Snai1 transcription. Importantly, high E2A and SNAIL1 expression occurred in aggressive human basal-like breast carcinomas, highlighting the relevance of the E2A-Snail1 axis in metastatic breast cancer. In addition, E2A factors contributed to the maintenance of genomic integrity and resistance to PARP inhibitors in PyMT and human triple-negative breast cancer cells. Collectively, these results support the potential for E2A transcription factors as novel targets worthy of translational consideration in breast cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2685
  5. Nat Commun. 2021 06 17. 12(1): 3636
    Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
    Diana Zatreanu, Helen M R Robinson, Omar Alkhatib, Marie Boursier, Harry Finch, Lerin Geo, Diego Grande, Vera Grinkevich, Robert A Heald, Sophie Langdon, Jayesh Majithiya, Claire McWhirter, Niall M B Martin, Shaun Moore, Joana Neves, Eeson Rajendra, Marco Ranzani, Theresia Schaedler, Martin Stockley, Kimberley Wiggins, Rachel Brough, Sandhya Sridhar, Aditi Gulati, Nan Shao, Luned M Badder, Daniela Novo, Eleanor G Knight, Rebecca Marlow, Syed Haider, Elsa Callen, Graeme Hewitt, Joost Schimmel, Remko Prevo, Christina Alli, Amanda Ferdinand, Cameron Bell, Peter Blencowe, Chris Bot, Mathew Calder, Mark Charles, Jayne Curry, Tennyson Ekwuru, Katherine Ewings, Wojciech Krajewski, Ellen MacDonald, Hollie McCarron, Leon Pang, Chris Pedder, Laurent Rigoreau, Martin Swarbrick, Ed Wheatley, Simon Willis, Ai Ching Wong, Andre Nussenzweig, Marcel Tijsterman, Andrew Tutt, Simon J Boulton, Geoff S Higgins, Stephen J Pettitt, Graeme C M Smith, Christopher J Lord.
      To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.
    DOI:  https://doi.org/10.1038/s41467-021-23463-8
  6. Oncogene. 2021 Jun 17.
    Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair.
    Josune Alonso-Marañón, Alberto Villanueva, Josep Maria Piulats, María Martínez-Iniesta, Laura Solé, Juan Martín-Liberal, Sonia Segura, Ramon M Pujol, Mar Iglesias, Anna Bigas, Fernando Gallardo, Lluís Espinosa.
      Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy in advanced stages. Chemotherapy has not demonstrated its efficacy in MM and current treatment for tumors carrying the most frequent BRAFV600E mutation consists of BRAF inhibitors alone or in combination with MAPK pathway inhibitors. We previously found that BRAF inhibition prevents activation of the DNA-damage repair (DDR) pathway in colorectal cancer thus potentiating the effect of chemotherapy. We now show that different chemotherapy agents inflict DNA damage in MM cells, which is efficiently repaired, associated with activation of the ATM-dependent DDR machinery. Pharmacologic inhibition of BRAF impairs ATM and DDR activation in these cells, leading to sustained DNA damage. Combination treatments involving DNA-damaging agents and BRAF inhibitors increase tumor cell death in vitro and in vivo, and impede MM regrowth after treatment cessation. We propose to reconsider the use of chemotherapy in combination with BRAF inhibitors for MM treatment.
    DOI:  https://doi.org/10.1038/s41388-021-01879-2
  7. Cancer Res. 2021 Jun 18. pii: canres.3543.2020. [Epub ahead of print]
    ENO1 promotes lung cancer metastasis via HGFR and WNT signaling-driven epithelial-mesenchymal transition.
    Hsin-Jung Li, Feng-Yi Ke, Chia-Ching Lin, Mei-Yi Lu, Yi-Huei Kuo, Yi-Ping Wang, Kang-Hao Liang, Shin-Chang Lin, Ya-Hsuan Chang, Hsuan-Yu Chen, Pan-Chyr Yang, Han-Chung Wu.
      ENO1 (α-enolase) expression is significantly correlated with reduced survival and poor prognosis in many cancer types, including lung cancer. However, the function of ENO1 in carcinogenesis remains elusive. In this study, we found that high expression of ENO1 is present in metastatic lung cancer cell lines and malignant tumors and is associated with poor overall survival of lung cancer patients. Knockdown of ENO1 decreased cancer cell proliferation and invasiveness, whereas overexpression of ENO1 enhanced these processes. Moreover, ENO1 expression promoted tumor growth in orthotopic models and enhanced lung tumor metastasis in tail-vein injection models. These effects were mediated by upregulation of mesenchymal markers N-cadherin and vimentin and the epithelial-mesenchymal transition (EMT) regulator SLUG, along with concurrent downregulation of E-cadherin. Mechanistically, ENO1 interacted with hepatocyte growth factor receptor (HGFR) and activated HGFR and Wnt signaling via increased phosphorylation of HGFR and the Wnt co-receptor LRP5/6. Activation of these signaling axes decreased GSK-3β activity via Src-PI3K-AKT signaling and inactivation of the β-catenin destruction complex to ultimately upregulate SLUG and β-catenin. Additionally, we generated a chimeric anti-ENO1 monoclonal antibody (chENO1-22) that can decrease cancer cell proliferation and invasion. chENO1-22 attenuated cancer cell invasion by inhibiting ENO1-mediated GSK3β inactivation to promote SLUG protein ubiquitination and degradation. Moreover, chENO1-22 prevented lung tumor metastasis and prolonged survival in animal models. Taken together, these findings illuminate the molecular mechanisms underlying the function of ENO1 in lung cancer metastasis and supports the therapeutic potential of a novel antibody targeting ENO1 for treating lung cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3543
  8. Cancer Discov. 2021 Jun 18.
    Single-Cell Lineage Tracing of Metastasis Uncovers an EMT Continuum.
      Metastatic cells occupied a continuum of EMT states, and aggression was highest in hybrid states.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-087
  9. Nat Commun. 2021 06 17. 12(1): 3720
    Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance.
    Haohao Huang, Songyang Zhang, Yuanyuan Li, Zhaodan Liu, Lanjuan Mi, Yan Cai, Xinzheng Wang, Lishu Chen, Haowen Ran, Dake Xiao, Fangye Li, Jiaqi Wu, Tingting Li, Qiuying Han, Liang Chen, Xin Pan, Huiyan Li, Tao Li, Kun He, Ailing Li, Xuemin Zhang, Tao Zhou, Qing Xia, Jianghong Man.
      Low levels of reactive oxygen species (ROS) are crucial for maintaining cancer stem cells (CSCs) and their ability to resist therapy, but the ROS regulatory mechanisms in CSCs remains to be explored. Here, we discover that prohibitin (PHB) specifically regulates mitochondrial ROS production in glioma stem-like cells (GSCs) and facilitates GSC radiotherapeutic resistance. We find that PHB is upregulated in GSCs and is associated with malignant gliomas progression and poor prognosis. PHB binds to peroxiredoxin3 (PRDX3), a mitochondrion-specific peroxidase, and stabilizes PRDX3 protein through the ubiquitin-proteasome pathway. Knockout of PHB dramatically elevates ROS levels, thereby inhibiting GSC self-renewal. Importantly, deletion or pharmacological inhibition of PHB potently slows tumor growth and sensitizes tumors to radiotherapy, thus providing significant survival benefits in GSC-derived orthotopic tumors and glioblastoma patient-derived xenografts. These results reveal a selective role of PHB in mitochondrial ROS regulation in GSCs and suggest that targeting PHB improves radiotherapeutic efficacy in glioblastoma.
    DOI:  https://doi.org/10.1038/s41467-021-24108-6
  10. Oncogene. 2021 Jun 18.
    LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit.
    Senlin Zhao, Bingjie Guan, Yushuai Mi, Debing Shi, Ping Wei, Yanzi Gu, Sanjun Cai, Ye Xu, Xinxiang Li, Dongwang Yan, Mingzhu Huang, Dawei Li.
      Glycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.
    DOI:  https://doi.org/10.1038/s41388-021-01859-6
  11. Trends Cancer. 2021 Jun 16. pii: S2405-8033(21)00107-2. [Epub ahead of print]
    Cancer cell adaptability: turning ribonucleoprotein granules into targets.
    Margot Lavalée, Nicolas Curdy, Camille Laurent, Jean-Jacques Fournié, Don-Marc Franchini.
      Stress granules (SGs) and processing bodies (P-bodies) are membraneless cytoplasmic condensates of ribonucleoproteins (RNPs). They both regulate RNA fate under physiological and pathological conditions, and are thereby involved in the regulation and maintenance of cellular integrity. During tumorigenesis, cancer cells use these granules to thrive, to adapt to the harsh conditions of the tumor microenvironment (TME), and to protect themselves from anticancer treatments. This ability to provide multiple outcomes not only makes RNP granules promising targets for cancer therapy but also emphasizes the need for more knowledge about the biology of these granules to achieve clinical use. In this review we focus on the role of RNP granules in cancer, and on how their composition and regulation might be used to elaborate therapeutic strategies.
    Keywords:  cancer; post-transcriptional regulation; processing bodies; stress granules; therapeutic target; translation
    DOI:  https://doi.org/10.1016/j.trecan.2021.05.006
  12. Cancer Cell. 2021 Jun 14. pii: S1535-6108(21)00273-7. [Epub ahead of print]39(6): 827-844.e10
    STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma.
    Biniam Adane, Gabriela Alexe, Bo Kyung A Seong, Diana Lu, Elizabeth E Hwang, Denes Hnisz, Caleb A Lareau, Linda Ross, Shan Lin, Filemon S Dela Cruz, Melissa Richardson, Abraham S Weintraub, Sarah Wang, Amanda Balboni Iniguez, Neekesh V Dharia, Amy Saur Conway, Amanda L Robichaud, Benjamin Tanenbaum, John M Krill-Burger, Francisca Vazquez, Monica Schenone, Jason N Berman, Andrew L Kung, Steven A Carr, Martin J Aryee, Richard A Young, Brian D Crompton, Kimberly Stegmaier.
      The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory, and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.
    Keywords:  EWS/FLI1; Ewing sarcoma; POU3F2; PRC2; STAG1; STAG2; cohesin; fusion oncoprotein; metastasis
    DOI:  https://doi.org/10.1016/j.ccell.2021.05.007
  13. Front Oncol. 2021 ;11 676135
    IP-10 (CXCL10) Can Trigger Emergence of Dormant Breast Cancer Cells in a Metastatic Liver Microenvironment.
    Amanda M Clark, Haley L Heusey, Linda G Griffith, Douglas A Lauffenburger, Alan Wells.
      Metastatic breast cancer remains a largely incurable and fatal disease with liver involvement bearing the worst prognosis. The danger is compounded by a subset of disseminated tumor cells that may lie dormant for years to decades before re-emerging as clinically detectable metastases. Pathophysiological signals can drive these tumor cells to emerge. Prior studies indicated CXCR3 ligands as being the predominant signals synergistically and significantly unregulated during inflammation in the gut-liver axis. Of the CXCR3 ligands, IP-10 (CXCL10) was the most abundant, correlated significantly with shortened survival of human breast cancer patients with metastatic disease and was highest in those with triple negative (TNBC) disease. Using a complex ex vivo all-human liver microphysiological (MPS) model of dormant-emergent metastatic progression, CXCR3 ligands were found to be elevated in actively growing populations of metastatic TNBC breast cancer cells whereas they remained similar to the tumor-free hepatic niche in those with dormant breast cancer cells. Subsequent stimulation of dormant breast cancer cells in the ex vivo metastatic liver MPS model with IP-10 triggered their emergence in a dose-dependent manner. Emergence was indicated to occur indirectly possibly via activation of the resident liver cells in the surrounding metastatic microenvironment, as stimulation of breast cancer cells with exogenous IP-10 did not significantly change their migratory, invasive or proliferative behavior. The findings reveal that IP-10 is capable of triggering the emergence of dormant breast cancer cells within the liver metastatic niche and identifies the IP-10/CXCR3 as a candidate targetable pathway for rational approaches aimed at maintaining dormancy.
    Keywords:   microphysiological system; CXCL10; IP-10; breast cancer dormancy; metastasis; organ-on-a-chip; tumor dormancy; tumor emergence
    DOI:  https://doi.org/10.3389/fonc.2021.676135
  14. Cell Death Differ. 2021 Jun 15.
    MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly.
    Yan Zhong, Ting Long, Chuan-Sha Gu, Jing-Yi Tang, Ling-Fang Gao, Jia-Xian Zhu, Zhi-Yan Hu, Xia Wang, Yi-Dan Ma, Yan-Qing Ding, Zu-Guo Li, Xiao-Yan Wang.
      Tumour metastasis is a major reason accounting for the poor prognosis of colorectal cancer (CRC), and the discovery of targets in the primary tumours that can predict the risk of CRC metastasis is now urgently needed. In this study, we identified autophagy-related protein 9B (ATG9B) as a key potential target gene for CRC metastasis. High expression of ATG9B in tumour significantly increased the risk of metastasis and poor prognosis of CRC. Mechanistically, we further find that ATG9B promoted CRC invasion mainly through autophagy-independent manner. MYH9 is the pivotal interacting protein for ATG9B functioning, which directly binds to cytoplasmic peptide segments aa368-411 of ATG9B by its head domain. Furthermore, the combination of ATG9B and MYH9 enhance the stability of each other by decreasing their binding to E3 ubiquitin ligase STUB1, therefore preventing them from ubiquitin-mediated degradation, which further amplified the effect of ATG9B and MYH9 in CRC cells. During CRC cell invasion, ATG9B is transported to the cell edge with the assistance of MYH9 and accelerates focal adhesion (FA) assembly through mediating the interaction of endocytosed integrin β1 and Talin-1, which facilitated to integrin β1 activation. Clinically, upregulated expression of ATG9B in human CRC tissue is always accompanied with highly elevated expression of MYH9 and associated with advanced CRC stage and poor prognosis. Taken together, this study highlighted the important role of ATG9B in CRC metastasis by promoting focal adhesion assembly, and ATG9B together with MYH9 can provide a pair of potential therapeutic targets for preventing CRC progression.
    DOI:  https://doi.org/10.1038/s41418-021-00813-z
  15. Cancer Cell. 2021 Jun 14. pii: S1535-6108(21)00282-8. [Epub ahead of print]39(6): 725-729
    Innate immune cells in the tumor microenvironment.
    Ming O Li, Natalie Wolf, David H Raulet, Leila Akkari, Mikael J Pittet, Paulo C Rodriguez, Rosandra N Kaplan, Ariel Munitz, Zemin Zhang, Sijin Cheng, Nina Bhardwaj.
      The tumor immune microenvironment (TIME) is a complex ecosystem that contains adaptive and innate immune cells that have tumor-promoting and anti-tumor effects. There is still much to learn about the diversity, plasticity, and functions of innate immune cells in the TIME and their roles in determining the response to immunotherapies. Experts discuss recent advances in our understanding of their biology in cancer as well as outstanding questions and potential therapeutic avenues.
    DOI:  https://doi.org/10.1016/j.ccell.2021.05.016
  16. J Immunother Cancer. 2021 Jun;pii: e002856. [Epub ahead of print]9(6):
    IL-6 contributes to metastatic switch via the differentiation of monocytic-dendritic progenitors into prometastatic immune cells.
    Ksenia Magidey-Klein, Tim J Cooper, Ksenya Kveler, Rachelly Normand, Tongwu Zhang, Michael Timaner, Ziv Raviv, Brian P James, Roi Gazit, Ze'ev A Ronai, Shai Shen-Orr, Yuval Shaked.
       BACKGROUND: Metastasis is the major cause of death in patients with cancer. Myeloid skewing of hematopoietic cells is a prominent promoter of metastasis. However, the reservoir of these cells in the bone marrow (BM) compartment and their differentiation pattern from hematopoietic stem and progenitor cells (HSPCs) have not been explored.
    METHODS: We used a unique model system consisting of tumor cell clones with low metastatic potential or high metastatic potential (met-low and met-high, respectively) to investigate the fate of HSPC differentiation using murine melanoma and breast carcinoma. Single-cell RNA sequencing (scRNA-seq) analysis was performed on HSPC obtained from the BM of met-low and met-high tumors. A proteomic screen of tumor-conditioned medium integrated with the scRNA-seq data analysis was performed to analyze the potential cross talk between cancer cells and HSPCs. Adoptive transfer of tumor-educated HSPC subsets obtained from green fluorescent protein (GFP)+ tagged mice was then carried out to identify the contribution of committed HSPCs to tumor spread. Peripheral mononuclear cells obtained from patients with breast and lung cancer were analyzed for HSPC subsets.
    RESULTS: Mice bearing met-high tumors exhibited a significant increase in the percentage of HSPCs in the BM in comparison with tumor-free mice or mice bearing met-low tumors. ScRNA-seq analysis of these HSPCs revealed that met-high tumors enriched the monocyte-dendritic progenitors (MDPs) but not granulocyte-monocyte progenitors (GMPs). A proteomic screen of tumor- conditioned medium integrated with the scRNA-seq data analysis revealed that the interleukin 6 (IL-6)-IL-6 receptor axis is highly active in HSPC-derived MDP cells. Consequently, loss of function and gain of function of IL-6 in tumor cells resulted in decreased and increased metastasis and corresponding MDP levels, respectively. Importantly, IL-6-educated MDPs induce metastasis within mice bearing met-low tumors-through further differentiation into immunosuppressive macrophages and not dendritic cells. Consistently, MDP but not GMP levels in peripheral blood of breast and lung cancer patients are correlated with tumor aggressiveness.
    CONCLUSIONS: Our study reveals a new role for tumor-derived IL-6 in hijacking the HSPC differentiation program toward prometastatic MDPs that functionally differentiate into immunosuppressive monocytes to support the metastatic switch.
    Keywords:  cellular; immunity; immunomodulation; macrophages; melanoma
    DOI:  https://doi.org/10.1136/jitc-2021-002856
  17. Nat Commun. 2021 06 17. 12(1): 3707
    BRN2 is a non-canonical melanoma tumor-suppressor.
    Michael Hamm, Pierre Sohier, Valérie Petit, Jérémy H Raymond, Véronique Delmas, Madeleine Le Coz, Franck Gesbert, Colin Kenny, Zackie Aktary, Marie Pouteaux, Florian Rambow, Alain Sarasin, Nisamanee Charoenchon, Alfonso Bellacosa, Luis Sanchez-Del-Campo, Laura Mosteo, Martin Lauss, Dies Meijer, Eirikur Steingrimsson, Göran B Jönsson, Robert A Cornell, Irwin Davidson, Colin R Goding, Lionel Larue.
      While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600E PtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.
    DOI:  https://doi.org/10.1038/s41467-021-23973-5
  18. Leukemia. 2021 Jun 12.
    Metabolic alterations mediated by STAT3 promotes drug persistence in CML.
    Sweta B Patel, Travis Nemkov, Davide Stefanoni, Gloria A Benavides, Mahmoud A Bassal, Brittany L Crown, Victoria R Matkins, Virginia Camacho, Valeriya Kuznetsova, Ashley T Hoang, Danielle E Tenen, Samuel L Wolock, Jihye Park, Li Ying, Zongliang Yue, Jake Y Chen, Henry Yang, Daniel G Tenen, Paul Brent Ferrell, Rui Lu, Victor Darley-Usmar, Angelo D'Alessandro, Ravi Bhatia, Robert S Welner.
      Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.
    DOI:  https://doi.org/10.1038/s41375-021-01315-0
  19. EMBO Mol Med. 2021 Jun 15. e14393
    Immunological barriers to immunotherapy in primary and metastatic breast cancer.
    Mara De Martino, Claire Vanpouille-Box, Lorenzo Galluzzi.
      Patients with breast cancer obtain limited clinical benefits from immune checkpoint inhibitors (ICIs), pointing to the existence of multiple immunological alterations that cannot be simultaneously normalized with immunotherapy. Accumulating preclinical evidence suggests that radiation therapy (RT) can be harnessed to sensitize primary and metastatic mouse mammary carcinomas to ICIs. However, various clinical trials combining RT with ICIs in patients with breast cancer documented little cooperativity. Here, we discuss immunological barriers that may prevent RT from unlocking the therapeutic potential of ICIs in patients with breast cancer. These observations may inspire the development of combinatorial regimens that might benefit patients with diverse neoplastic conditions including brain tumors.
    Keywords:  CTLA4; MPA/DMBA-driven carcinomas; PD-1; TGF-β; glioblastoma
    DOI:  https://doi.org/10.15252/emmm.202114393
  20. Nat Commun. 2021 06 15. 12(1): 3651
    IL-6 regulates autophagy and chemotherapy resistance by promoting BECN1 phosphorylation.
    Fuqing Hu, Da Song, Yumeng Yan, Changsheng Huang, Chentao Shen, Jingqin Lan, Yaqi Chen, Anyi Liu, Qi Wu, Li Sun, Feng Xu, Fayong Hu, Lisheng Chen, Xuelai Luo, Yongdong Feng, Shengyou Huang, Junbo Hu, Guihua Wang.
      Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-021-23923-1
  21. Nature. 2021 Jun 16.
    Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.
    María Casanova-Acebes, Erica Dalla, Andrew M Leader, Jessica LeBerichel, Jovan Nikolic, Blanca M Morales, Markus Brown, Christie Chang, Leanna Troncoso, Steven T Chen, Ana Sastre-Perona, Matthew D Park, Alexandra Tabachnikova, Maxime Dhainaut, Pauline Hamon, Barbara Maier, Catherine M Sawai, Esperanza Agulló-Pascual, Markus Schober, Brian D Brown, Boris Reizis, Thomas Marron, Ephraim Kenigsberg, Christine Moussion, Philippe Benaroch, Julio A Aguirre-Ghiso, Miriam Merad.
      Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
    DOI:  https://doi.org/10.1038/s41586-021-03651-8
  22. Nat Commun. 2021 06 10. 12(1): 3528
    Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance.
    Chisato M Yamazaki, Aiko Yamaguchi, Yasuaki Anami, Wei Xiong, Yoshihiro Otani, Jangsoon Lee, Naoto T Ueno, Ningyan Zhang, Zhiqiang An, Kyoji Tsuchikama.
      Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.
    DOI:  https://doi.org/10.1038/s41467-021-23793-7
  23. Commun Biol. 2021 Jun 16. 4(1): 747
    When dormancy fuels tumour relapse.
    Karla Santos-de-Frutos, Nabil Djouder.
      Tumour recurrence is a serious impediment to cancer treatment, but the mechanisms involved are poorly understood. The most frequently used anti-tumour therapies-chemotherapy and radiotherapy-target highly proliferative cancer cells. However non- or slow-proliferative dormant cancer cells can persist after treatment, eventually causing tumour relapse. Whereas the reversible growth arrest mechanism allows quiescent cells to re-enter the cell cycle, senescent cells are largely thought to be irreversibly arrested, and may instead contribute to tumour growth and relapse through paracrine signalling mechanisms. Thus, due to the differences in their growth arrest mechanism, metabolic features, plasticity and adaptation to their respective tumour microenvironment, dormant-senescent and -quiescent cancer cells could have different but complementary roles in fuelling tumour growth. In this review article, we discuss the implication of dormant cancer cells in tumour relapse and the need to understand how quiescent and senescent cells, respectively, may play a part in this process.
    DOI:  https://doi.org/10.1038/s42003-021-02257-0
  24. Cancer Cell. 2021 Jun 14. pii: S1535-6108(21)00279-8. [Epub ahead of print]39(6): 738-742
    Eradicating micrometastases with immune checkpoint blockade: Strike while the iron is hot.
    Yelena Y Janjigian, Jedd D Wolchok, Charlotte E Ariyan.
      Immune checkpoint blockade (ICB) is transforming treatment for many cancers. While ICB alone initially demonstrated efficacy in patients with metastatic melanoma, it has expanded to other types and to earlier-stage cancers. We describe ICB history, mechanisms underlying variation in response, and how ICB is being integrated into adjuvant and neoadjuvant treatment approaches.
    DOI:  https://doi.org/10.1016/j.ccell.2021.05.013
  25. Nat Commun. 2021 Jun 18. 12(1): 3742
    Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells.
    Patrick D Rädler, Barbara L Wehde, Aleata A Triplett, Hridaya Shrestha, Jonathan H Shepherd, Adam D Pfefferle, Hallgeir Rui, Robert D Cardiff, Charles M Perou, Kay-Uwe Wagner.
      Claudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.
    DOI:  https://doi.org/10.1038/s41467-021-23957-5
  26. Cancer Res. 2021 Jun 14.
    Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate.
    Judith Goncalves, Sophie Moog, Aurélie Morin, Géraldine Gentric, Sebastian Müller, Alexander P Morrell, Katarina Kluckova, Theodora J Stewart, Cynthia L Andoniadou, Charlotte Lussey-Lepoutre, Paule Bénit, Alpesh Thakker, Lisa Vettore, Jennie Roberts, Raphaël Rodriguez, Fatima Mechta-Grigoriou, Anne-Paule Gimenez-Roqueplo, Eric Letouzé, Daniel A Tennant, Judith Favier.
      Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an Sdhd knockout chromaffin cell line and compared it with Sdhb-deficient cells. Both cell types exhibited similar SDH loss of function, metabolic adaptation, and succinate accumulation. In contrast, Sdhb-/- cells showed hallmarks of mesenchymal transition associated with increased DNA hypermethylation and a stronger pseudo-hypoxic phenotype compared with Sdhd-/- cells. Loss of SDHB specifically led to increased oxidative stress associated with dysregulated iron and copper homeostasis in the absence of NRF2 activation. High-dose ascorbate exacerbated the increase in mitochondrial reactive oxygen species, leading to cell death in Sdhb-/- cells. These data establish a mechanism linking oxidative stress to iron homeostasis that specifically occurs in Sdhb-deficient cells and may promote metastasis. They also highlight high-dose ascorbate as a promising therapeutic strategy for SDHB-related cancers. SIGNIFICANCE: Loss of different succinate dehydrogenase subunits can lead to different cell and tumor phenotypes, linking stronger 2-OG-dependent dioxygenases inhibition, iron overload, and ROS accumulation following SDHB mutation.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-2936
  27. Nat Commun. 2021 Jun 18. 12(1): 3766
    Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer.
    Ken-Ichi Takayama, Takeo Kosaka, Takashi Suzuki, Hiroshi Hongo, Mototsugu Oya, Tetsuya Fujimura, Yutaka Suzuki, Satoshi Inoue.
      Interactive networks of transcription factors (TFs) have critical roles in epigenetic and gene regulation for cancer progression. It is required to clarify underlying mechanisms for transcriptional activation through concerted efforts of TFs. Here, we show the essential role of disease phase-specific TF collaboration changes in advanced prostate cancer (PC). Investigation of the transcriptome in castration-resistant PC (CRPC) revealed OCT4 as a key TF in the disease pathology. OCT4 confers epigenetic changes by promoting complex formation with FOXA1 and androgen receptor (AR), the central signals for the progression to CRPC. Meanwhile, OCT4 facilitates a distinctive complex formation with nuclear respiratory factor 1 (NRF1) to gain chemo-resistance in the absence of AR. Mechanistically, we reveal that OCT4 increases large droplet formations with AR/FOXA1 as well as NRF1 in vitro. Disruption of TF collaborations using a nucleoside analogue, ribavirin, inhibited treatment-resistant PC tumor growth. Thus, our findings highlight the formation of TF collaborations as a potent therapeutic target in advanced cancer.
    DOI:  https://doi.org/10.1038/s41467-021-23974-4
  28. Nat Med. 2021 Jun 17.
    Preventing breast cancer recurrence.
    Karen O'Leary.
      
    Keywords:  Breast cancer; Clinical trials; Targeted therapies
    DOI:  https://doi.org/10.1038/d41591-021-00041-5
  29. Trends Cancer. 2021 Jun 07. pii: S2405-8033(21)00104-7. [Epub ahead of print]
    Autophagy Regulates Stress Responses, Metabolism, and Anticancer Immunity.
    Eileen White, Edmund C Lattime, Jessie Yanxiang Guo.
      Autophagy is a catabolic intracellular nutrient-scavenging pathway triggered by nutrient deprivation and stress that captures and degrades intracellular proteins and organelles in lysosomes. The breakdown products are then recycled into metabolic pathways to sustain survival. Organelle turnover by autophagy contributes to quality control and suppresses inflammation. Autophagy is upregulated in many cancers and supports their growth, survival, and malignancy in a tumor cell-autonomous fashion. Host autophagy also promotes tumor growth by maintaining a supply of essential nutrients and suppressing innate and adaptive antitumor immune responses. Autophagy is also upregulated in response to cancer therapy and confers treatment resistance. Thus, autophagy is a cancer vulnerability and its inhibition is under investigation as a novel therapeutic approach.
    Keywords:  T cells; autophagy; cancer; immune response; interferon; metabolism
    DOI:  https://doi.org/10.1016/j.trecan.2021.05.003
  30. Clin Cancer Res. 2021 Jun 15. pii: clincanres.0572.2021. [Epub ahead of print]
    Complementary role of circulating tumor DNA assessment and tissue genomic profiling in metastatic renal cell carcinoma.
    Zeynep B Zengin, Caroline Weipert, Nicholas J Salgia, Nazli Dizman, Joann Hsu, Luis Meza, Alexander Chehrazi-Raffle, Ramya Muddasani, Sabrina Salgia, Jasnoor Malhotra, Neal Chawla, Errol J Philip, Lesli Kiedrowski, Benjamin L Maughan, Nityam Rathi, Divyam Goel, Toni K Choueiri, Neeraj Agarwal, Sumanta K Pal.
       PURPOSE: The role of circulating cell-free tumor DNA (ctDNA) as an adjunct to tissue genomic profiling is poorly defined in metastatic renal cell carcinoma (mRCC). In this study we aim to validate previous findings related to genomic alteration (GA) frequency in ctDNA and determine the concordance between ctDNA and tissue-based profiling in patients with mRCC.
    EXPERIMENTAL DESIGN: Results of 839 mRCC patients who had ctDNA assessment with a CLIA-certified ctDNA assay between November 2016 and December 2019 were collected. Tissue-based genomic profiling was collected when available and concordance analysis between blood- and tissue-based testing was performed.
    RESULTS: ctDNA was assessed in 839 patients (comprising 920 samples) with mRCC. GAs were detected in 661 samples (71.8%). Tissue-based GAs were assessed in 112 patients. Limiting our analyses to a common 73-/74-gene set and excluding samples with no ctDNA detected, a total of 228 mutations were found in tissue and blood. 34.7% (42/121) of the mutations identified in tissue were also identified via ctDNA, while 28.2% (42/149) of the mutations identified in liquid were also identified via tissue. Concordance between ctDNA and tissue-based profiling was inversely related to the time elapsed between these assays.
    CONCLUSIONS: This study confirms the feasibility of ctDNA profiling in the largest mRCC cohort to date, with ctDNA identifying multiple actionable alterations. It also demonstrates that ctDNA and tissue-based genomic profiling are complementary, with both platforms identifying unique alterations, and confirms that the frequency of unique alterations increases with greater temporal separation between tests.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-0572
  31. Elife. 2021 Jun 11. pii: e66222. [Epub ahead of print]10
    A systematic CRISPR screen reveals an IL-20/IL20RA-mediated immune crosstalk to prevent the ovarian cancer metastasis.
    Jia Li, Xuan Qin, Jie Shi, Xiaoshuang Wang, Tong Li, Mengyao Xu, Xiaosu Chen, Yujia Zhao, Jiahao Han, Yongjun Piao, Wenwen Zhang, Pengpeng Qu, Longlong Wang, Rong Xiang, Yi Shi.
      Transcoelomic spread of cancer cells across the peritoneal cavity occurs in most initially diagnosed ovarian cancer (OC) patients and accounts for most cancer-related death. However, how OC cells interact with peritoneal stromal cells to evade the immune surveillance remains largely unexplored. Here, through an in vivo genome-wide CRISPR/Cas9 screen, we identified IL20RA, which decreased dramatically in OC patients during peritoneal metastasis, as a key factor preventing the transcoelomic metastasis of OC. Reconstitution of IL20RA in highly metastatic OC cells greatly suppresses the transcoelomic metastasis. OC cells, when disseminate into the peritoneal cavity, greatly induce peritoneum mesothelial cells to express IL-20 and IL-24, which in turn activate the IL20RA downstream signaling in OC cells to produce mature IL-18, eventually resulting in the polarization of macrophages into the M1-like subtype to clear the cancer cells. Thus, we show an IL-20/IL20RA-mediated crosstalk between OC and mesothelial cells that supports a metastasis-repressing immune microenvironment.
    Keywords:  IL-18; IL-20; IL20RA; cancer biology; human; immune crosstalk; metastasis; mouse; ovarian cancer
    DOI:  https://doi.org/10.7554/eLife.66222
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