bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2021–04–04
27 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress.
  2. EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells.
  3. Metastasis-Initiating Cells and Ecosystems.
  4. Overcoming Resistance to Tumor-Targeted and Immune-Targeted Therapies.
  5. N6-methyladenosine regulates mRNA stability and translation efficiency of KRT7 to promote breast cancer lung metastasis.
  6. Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response.
  7. Therapy resistance on the RADar in ovarian cancer.
  8. FOSL1 Promotes Metastasis of Head and Neck Squamous Cell Carcinoma Through Super-Enhancer-Driven Transcription Program.
  9. Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells.
  10. m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.
  11. Targeting AXL Kinase Sensitizes Leukemic Stem and Progenitor Cells to Venetoclax Treatment in Acute Myeloid Leukemia.
  12. MYC-activated lncRNA MNX1-AS1 promotes the progression of colorectal cancer by stabilizing YB1.
  13. Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer.
  14. ATP11B mediates platinum resistance in ovarian cancer.
  15. Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth.
  16. Autophagy Dependent Sensitization of Triple Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of The Nucleosome Remodeling Factor.
  17. SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance.
  18. Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness.
  19. Cytotoxic Immune Cells Suppress Metastasis via Mechanical Sensing.
  20. Liquid Biopsy: From Discovery to Clinical Application.
  21. Emerging Trends in Cancer Drug Discovery-From Drugging the "Undruggable" to Overcoming Resistance.
  22. The Functional GRHL3-Filaggrin Axis Maintains a Tumour Differentiation Potential and Influences Drug Sensitivity.
  23. The Promising Evolution of Targeted Therapeutic Strategies in Cancer.
  24. Decoding Cancer Biology One Cell at a Time.
  25. Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver.
  26. E2F2 drives glioma progression via PI3K/AKT in a PFKFB4-dependent manner.
  27. Genomic, Transcriptomic and Proteomic Profiling of Metastatic Breast Cancer.
  1. Cancers (Basel). 2021 Mar 18. pii: 1366. [Epub ahead of print]13(6):
    Osteoblast-Derived Paracrine and Juxtacrine Signals Protect Disseminated Breast Cancer Cells from Stress.
    Russell Hughes, Xinyue Chen, Natasha Cowley, Penelope D Ottewell, Rhoda J Hawkins, Keith D Hunter, Jamie K Hobbs, Nicola J Brown, Ingunn Holen.
      Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth.
    Keywords:  breast cancer; dormancy; latency; metastasis; skeletal
    DOI:  https://doi.org/10.3390/cancers13061366
  2. Cancers (Basel). 2021 Mar 03. pii: 1079. [Epub ahead of print]13(5):
    EphB6 Regulates TFEB-Lysosomal Pathway and Survival of Disseminated Indolent Breast Cancer Cells.
    Manuela Zangrossi, Patrizia Romani, Probir Chakravarty, Colin D H Ratcliffe, Steven Hooper, Martina Dori, Mattia Forcato, Silvio Bicciato, Sirio Dupont, Erik Sahai, Marco Montagner.
      Late relapse of disseminated cancer cells is a common feature of breast and prostate tumors. Several intrinsic and extrinsic factors have been shown to affect quiescence and reawakening of disseminated dormant cancer cells (DDCCs); however, the signals and processes sustaining the survival of DDCCs in a foreign environment are still poorly understood. We have recently shown that crosstalk with lung epithelial cells promotes survival of DDCCs of estrogen receptor-positive (ER+) breast tumors. By using a lung organotypic system and in vivo dissemination assays, here we show that the TFEB-lysosomal axis is activated in DDCCs and that it is modulated by the pro-survival ephrin receptor EphB6. TFEB lysosomal direct targets are enriched in DDCCs in vivo and correlate with relapse in ER+ breast cancer patients. Direct coculture of DDCCs with alveolar type I-like lung epithelial cells and dissemination in the lung drive lysosomal accumulation and EphB6 induction. EphB6 contributes to survival, TFEB transcriptional activity, and lysosome formation in DDCCs in vitro and in vivo. Furthermore, signaling from EphB6 promotes the proliferation of surrounding lung parenchymal cells in vivo. Our data provide evidence that EphB6 is a key factor in the crosstalk between disseminated dormant cancer cells and the lung parenchyma and that the TFEB-lysosomal pathway plays an important role in the persistence of DDCCs.
    Keywords:  EphB6; Ephrin receptors; breast cancer; dormancy; lysosomes; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers13051079
  3. Cancer Discov. 2021 Apr;11(4): 971-994
    Metastasis-Initiating Cells and Ecosystems.
    Joan Massagué, Karuna Ganesh.
      Metastasis is initiated and sustained through therapy by cancer cells with stem-like and immune-evasive properties, termed metastasis-initiating cells (MIC). Recent progress suggests that MICs result from the adoption of a normal regenerative progenitor phenotype by malignant cells, a phenotype with intrinsic programs to survive the stresses of the metastatic process, undergo epithelial-mesenchymal transitions, enter slow-cycling states for dormancy, evade immune surveillance, establish supportive interactions with organ-specific niches, and co-opt systemic factors for growth and recurrence after therapy. Mechanistic understanding of the molecular mediators of MIC phenotypes and host tissue ecosystems could yield cancer therapeutics to improve patient outcomes. SIGNIFICANCE: Understanding the origins, traits, and vulnerabilities of progenitor cancer cells with the capacity to initiate metastasis in distant organs, and the host microenvironments that support the ability of these cells to evade immune surveillance and regenerate the tumor, is critical for developing strategies to improve the prevention and treatment of advanced cancer. Leveraging recent progress in our understanding of the metastatic process, here we review the nature of MICs and their ecosystems and offer a perspective on how this knowledge is informing innovative treatments of metastatic cancers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0010
  4. Cancer Discov. 2021 Apr;11(4): 874-899
    Overcoming Resistance to Tumor-Targeted and Immune-Targeted Therapies.
    Mihaela Aldea, Fabrice Andre, Aurelien Marabelle, Semih Dogan, Fabrice Barlesi, Jean-Charles Soria.
      Resistance to anticancer therapies includes primary resistance, usually related to lack of target dependency or presence of additional targets, and secondary resistance, mostly driven by adaptation of the cancer cell to the selection pressure of treatment. Resistance to targeted therapy is frequently acquired, driven by on-target, bypass alterations, or cellular plasticity. Resistance to immunotherapy is often primary, orchestrated by sophisticated tumor-host-microenvironment interactions, but could also occur after initial efficacy, mostly when only partial responses are obtained. Here, we provide an overview of resistance to tumor and immune-targeted therapies and discuss challenges of overcoming resistance, and current and future directions of development. SIGNIFICANCE: A better and earlier identification of cancer-resistance mechanisms could avoid the use of ineffective drugs in patients not responding to therapy and provide the rationale for the administration of personalized drug associations. A clear description of the molecular interplayers is a prerequisite to the development of novel and dedicated anticancer drugs. Finally, the implementation of such cancer molecular and immunologic explorations in prospective clinical trials could de-risk the demonstration of more effective anticancer strategies in randomized registration trials, and bring us closer to the promise of cure.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1638
  5. Cancer Res. 2021 Apr 01. pii: canres.3779.2020. [Epub ahead of print]
    N6-methyladenosine regulates mRNA stability and translation efficiency of KRT7 to promote breast cancer lung metastasis.
    Feng Chen, Zhuojia Chen, Tao Guan, Yan Zhou, Lichen Ge, Haisheng Zhang, Yingmin Wu, Guan-Min Jiang, Weiling He, Jiexin Li, Hongsheng Wang.
      The roles of RNA modification during organ metastasis of cancer cells are not known. Here we established breast cancer (BC) lung metastasis cells by three rounds of selection of lung metastatic subpopulations in vivo and designated them BCLMF3 cells. In these cells, mRNA N6-methyladenosine (m6A) and methyltransferase METTL3 were increased, while the demethylase FTO was decreased. Epi-transcriptome and transcriptome analyses together with functional studies identified keratin 7 (KRT7) as a key effector for m6A-induced BC lung metastasis. Specifically, increased METTL3 methylated KRT7-AS at A877 to increase the stability of a KRT7-AS/KRT7 mRNA duplex via IGF2BP1/HuR complexes. Furthermore, YTHDF1/eEF-1 was involved in FTO-regulated translational elongation of KRT7 mRNA, with methylated A950 in KRT7 exon 6 as the key site for methylation. In vivo and clinical studies confirmed the essential roles of KRT7, KRT7-AS, and METTL3 for lung metastasis and clinical progression of breast cancer. Collectively, m6A promotes BC lung metastasis by increasing the stability of a KRT7-AS/KRT7 mRNA duplex and translation of KRT7.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3779
  6. Nat Commun. 2021 Mar 31. 12(1): 1998
    Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response.
    IMAXT Consortium
      The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.
    DOI:  https://doi.org/10.1038/s41467-021-22303-z
  7. EMBO Mol Med. 2021 Mar 29. e14010
    Therapy resistance on the RADar in ovarian cancer.
    Jonas Schwickert, Franziska M Zickgraf, Martin R Sprick.
      Ovarian cancer has the worst prognosis of all gynecological cancers with high-grade serous ovarian cancer (HGSOC) accounting for the majority of ovarian cancer deaths. Therapy resistance and the selection of effective therapies for patients remains a major challenge. In this issue of EMBO Molecular Medicine, Hoppe et al present RAD51 expression as a biomarker of platinum resistance in high-grade serous ovarian cancer (HGSOC) patients (Hoppe et al, 2021).
    DOI:  https://doi.org/10.15252/emmm.202114010
  8. Mol Ther. 2021 Mar 29. pii: S1525-0016(21)00153-2. [Epub ahead of print]
    FOSL1 Promotes Metastasis of Head and Neck Squamous Cell Carcinoma Through Super-Enhancer-Driven Transcription Program.
    Ming Zhang, Rosalie G Hoyle, Zhikun Ma, Bo Sun, Weixin Cai, Hongshi Cai, Nan Xie, Yadong Zhang, Jinsong Hou, Xiqiang Liu, Demeng Chen, Glen E Kellogg, Hisashi Harada, Yue Sun, Cheng Wang, Jiong Li.
      Previously, we discovered that FOSL1 facilitates the metastasis of head and neck squamous cell carcinoma (HNSCC) cancer stem cells in a spontaneous mouse model. However, the molecular mechanisms remained unclear. Here, we demonstrated that FOSL1 serves as the dominate AP1 family member and is significantly upregulated in HNSCC tumor tissues and correlated with metastasis of HNSCC. Mechanistically, FOSL1 exerts its function in promoting tumorigenicity and metastasis predominantly via selective association with Mediators to establish super-enhancers (SEs) at a cohort of cancer stemness and pro-metastatic genes, such as SNAI2 and FOSL1 itself. Depletion of FOSL1 led to disruption of SEs and expression inhibition of these key oncogenes, which resulted in the suppression of tumor-initiation and metastasis. We also revealed that the abundance of FOSL1 is positively associated with the abundance of SNAI2 in HNSCC and the high expression of FOSL1 and SNAI2 levels are associated with short overall disease-free survival. Finally, the administration of the FOSL1 inhibitor, SR11302, significantly suppressed tumor growth and lymph node metastasis of HNSCC in a patient-derived-xenograft model. These findings indicate that FOSL1 is a master regulator that promotes the metastasis of HNSCC through a SE-driven transcription program that may represent an attractive target for therapeutic interventions.
    DOI:  https://doi.org/10.1016/j.ymthe.2021.03.024
  9. Cancers (Basel). 2021 Mar 05. pii: 1118. [Epub ahead of print]13(5):
    Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells.
    Giulia De Conti, Matheus Henrique Dias, René Bernards.
      Designing specific therapies for drug-resistant cancers is arguably the ultimate challenge in cancer therapy. While much emphasis has been put on the study of genetic alterations that give rise to drug resistance, much less is known about the non-genetic adaptation mechanisms that operate during the early stages of drug resistance development. Drug-tolerant persister cells have been suggested to be key players in this process. These cells are thought to have undergone non-genetic adaptations that enable survival in the presence of a drug, from which full-blown resistant cells may emerge. Such initial adaptations often involve engagement of stress response programs to maintain cancer cell viability. In this review, we discuss the nature of drug-tolerant cancer phenotypes, as well as the non-genetic adaptations involved. We also discuss how malignant cells employ homeostatic stress response pathways to mitigate the intrinsic costs of such adaptations. Lastly, we discuss which vulnerabilities are introduced by these adaptations and how these might be exploited therapeutically.
    Keywords:  adaptive resistance; cellular plasticity; collateral vulnerability; drug tolerance; stress response
    DOI:  https://doi.org/10.3390/cancers13051118
  10. Nat Cell Biol. 2021 Apr 01.
    m6A-independent genome-wide METTL3 and METTL14 redistribution drives the senescence-associated secretory phenotype.
    Pingyu Liu, Fuming Li, Jianhuang Lin, Takeshi Fukumoto, Timothy Nacarelli, Xue Hao, Andrew V Kossenkov, M Celeste Simon, Rugang Zhang.
      Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex that catalyses messenger RNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent functions of the methyltransferase complex, the m6A-independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 transcriptionally drives the senescence-associated secretory phenotype (SASP) in an m6A-independent manner. METTL14 is redistributed to the enhancers, whereas METTL3 is localized to the pre-existing NF-κB sites within the promoters of SASP genes during senescence. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL3 and METTL14 are required for both the tumour-promoting and immune-surveillance functions of senescent cells, which are mediated by SASP in vivo in mouse models. In summary, our results report an m6A-independent function of the METTL3 and METTL14 complex in transcriptionally promoting SASP during senescence.
    DOI:  https://doi.org/10.1038/s41556-021-00656-3
  11. Blood. 2021 Mar 30. pii: blood.2020007651. [Epub ahead of print]
    Targeting AXL Kinase Sensitizes Leukemic Stem and Progenitor Cells to Venetoclax Treatment in Acute Myeloid Leukemia.
    Xiaojia Niu, Katharina Rothe, Min Chen, Sarah Grasedieck, Rick Li, Sung-Eun Nam, Xiuyan Zhang, German Novakovskiy, Ye-Hyeon Ahn, Irina A Maksakova, Shenshen Lai, Hong Zhang, Jun Yan, Hong Liu, Yun Zhao, Depei Wu, Yubin Ge, Wyeth Wasserman, Arefeh Rouhi, Florian Christoph Kuchenbauer, Calvin K Yip, Zaihui Zhang, Xiaoyan Jiang.
      The abundance of genetic abnormalities and phenotypic heterogeneities in AML pose significant challenges to developing improved treatments. Here we demonstrated that a key GAS6/AXL axis is highly activated in AML patient cells, particularly in stem/progenitor cells. We developed a potent, selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition or in combination with venetoclax potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells, which shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have direct translational impact on the treatment of AML and other cancers with high AXL activity.
    DOI:  https://doi.org/10.1182/blood.2020007651
  12. Cancer Res. 2021 Mar 29. pii: canres.3747.2020. [Epub ahead of print]
    MYC-activated lncRNA MNX1-AS1 promotes the progression of colorectal cancer by stabilizing YB1.
    Qi-Nian Wu, Xiao-Jing Luo, Jia Liu, Yun-Xin Lu, Yun Wang, Jingjing Qi, Ze-Xian Liu, Qitao Huang, Zekun Liu, Jiabin Lu, Ying Jin, Heng-Ying Pu, Pei-Shan Hu, Jia-Bo Zheng, Zhao-Lei Zeng, Huai-Qiang Ju, Dan Xie, Qi Zhao, Rui-Hua Xu.
      Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer (CRC) are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer-related lncRNA, MNX1-AS1. MNX1-AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1-AS1 promotes the proliferation of CRC cells. MNX1-AS1 bound to and activated Y-box-binding protein 1 (YB1), a multifunctional RNA/DNA-binding protein, and prevented its ubiquitination and degradation. A marked overlap between genes that are differentially expressed in MNX1-AS1 knockdown cells and transcriptional targets of YB1 was observed. YB1 knockdown mimicked the loss of viability phenotype observed upon depletion of MNX1-AS1. In addition, MYC bound the promoter of the MNX1-AS1 locus and activated its transcription. In vivo experiments showed that ASO inhibited MNX1-AS1, which suppressed the proliferation of CRC cells in both cell-based and patient-derived xenograft (PDX) models. Collectively, these findings suggest that the MYC-MNX1-AS1-YB1 axis might serve as a potential biomarker and therapeutic target in CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-3747
  13. Oncogene. 2021 Apr 01.
    Targeting the glucocorticoid receptor signature gene Mono Amine Oxidase-A enhances the efficacy of chemo- and anti-androgen therapy in advanced prostate cancer.
    Martin Puhr, Andrea Eigentler, Florian Handle, Hubert Hackl, Christian Ploner, Isabel Heidegger, Georg Schaefer, Maximilian P Brandt, Julia Hoefer, Gabri Van der Pluijm, Helmut Klocker.
      Despite increasing options for treatment of castration-resistant prostate cancer, development of drug resistance is inevitable. The glucocorticoid receptor (GR) is a prime suspect for acquired therapy resistance, as prostate cancer (PCa) cells are able to increase GR signaling during anti-androgen therapy and thereby circumvent androgen receptor (AR)-blockade and cell death. As standard AR-directed therapies fail to block the GR and GR inhibitors might result in intolerable side effects, the identification of GR signature genes, which are better suited for a targeted approach, is of clinical importance. Therefore, the specific epithelial and stromal GR signature was determined in cancer-associated fibroblasts as well as in abiraterone and enzalutamide-resistant cells after glucocorticoid (GC) treatment. Microarray and ChIP analysis identified MAO-A as a directly up-regulated mutual epithelial and stromal GR target, which is induced after GC treatment and during PCa progression. Elevated MAO-A levels were confirmed in in vitro cell models, in primary tissue cultures after GC treatment, and in patients after neoadjuvant chemotherapy with GCs. MAO-A expression correlates with GR/AR activity as well as with a reduced progression-free survival. Pharmacological MAO-A inhibition combined with 2nd generation AR signaling inhibitors or chemotherapeutics results in impaired growth of androgen-dependent, androgen-independent, and long-term anti-androgen-treated cells. In summary, these findings demonstrate that targeting MAO-A represents an innovative therapeutic strategy to synergistically block GR and AR dependent PCa cell growth and thereby overcome therapy resistance.
    DOI:  https://doi.org/10.1038/s41388-021-01754-0
  14. J Clin Invest. 2021 Apr 01. pii: 149893. [Epub ahead of print]131(7):
    ATP11B mediates platinum resistance in ovarian cancer.
    Myrthala Moreno-Smith, J B Halder, Paul S Meltzer, Tamas A Gonda, Lingegowda S Mangala, Rajesha Rupaimoole, Chunhua Lu, Archana S Nagaraja, Kshipra M Gharpure, Yu Kang, Cristian Rodriguez-Aguayo, Pablo E Vivas-Mejia, Behrouz Zand, Rosemarie Schmandt, Hua Wang, Robert R Langley, Nicholas B Jennings, Cristina Ivan, Jeremy E Coffin, Guillermo N Armaiz, Justin Bottsford-Miller, Sang Bae Kim, Margaret S Halleck, Mary Jc Hendrix, William Bornman, Menashe Bar-Eli, Ju-Seog Lee, Zahid H Siddik, Gabriel Lopez-Berestein, Anil K Sood.
      
    DOI:  https://doi.org/10.1172/JCI149893
  15. Int J Mol Sci. 2021 Mar 13. pii: 2911. [Epub ahead of print]22(6):
    Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth.
    Lauren M Kreps, Christina L Addison.
      Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases.
    Keywords:  MDSC; angiogenesis; bone metastasis; bone remodeling; dormancy; immunosuppression; macrophage; osteoblast; osteoclast; therapy
    DOI:  https://doi.org/10.3390/ijms22062911
  16. Mol Cancer Res. 2021 Apr 02. pii: molcanres.0743.2020. [Epub ahead of print]
    Autophagy Dependent Sensitization of Triple Negative Breast Cancer Models to Topoisomerase II Poisons by Inhibition of The Nucleosome Remodeling Factor.
    Liliya Tyutyunyk-Massey, Yilun Sun, Nga Dao, Hannah Ngo, Mallika Dammalapati, Ashish Vaidyanathan, Manjulata Singh, Syed Haqqani, Joshua Haueis, Ryan Finnegan, Deng Xiaoyan, Steven Kirberger, Paula Bos, Dipankar Bandyopadhyay, William Pomerantz, Yves Pommier, David Gewirtz, Joseph W Landry.
      Epigenetic regulators can modulate the effects of cancer therapeutics. To further these observations, we discovered that the bromodomain PHD finger transcription factor subunit (BPTF) of the nucleosome remodeling factor (NURF) promotes resistance to doxorubicin, etoposide and paclitaxel in the 4T1 breast tumor cell line. BPTF functions in promoting resistance to doxorubicin and etoposide, but not paclitaxel, and may be selective to cancer cells, as a similar effect was not observed in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown (KD) was associated with increased DNA damage, topoisomerase II (Top2) crosslinking and autophagy; however, there was only a modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic 4T1 breast tumor model using both genetic and pharmacological inhibition of BPTF. The effects of BPTF inhibition in vivo are autophagy dependent, based on genetic autophagy inhibition. Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231 but not ER positive 67NR and MCF7 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vitro sensitization to doxorubicin, increased Top2-DNA crosslinks and DNA damage. Taken together, these studies demonstrate that BPTF provides resistance to the antitumor activity of Top2 poisons, preventing the resolution of Top2 crosslinking and associated autophagy. These studies suggest that BPTF can be targeted with small molecule inhibitors to enhance the effectiveness of Top2-targeted cancer chemotherapeutic drugs. Implications: These studies suggest NURF can be inhibited pharmacologically as a viable strategy to improve chemotherapy effectiveness.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-20-0743
  17. Cell Death Dis. 2021 Apr 01. 12(4): 341
    SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance.
    Jing Li, Ruiqin Wu, Mingo M H Yung, Jing Sun, Zhuqing Li, Hai Yang, Yi Zhang, Stephanie S Liu, Annie N Y Cheung, Hextan Y S Ngan, John C Braisted, Wei Zheng, Huiqiang Wei, Yingtang Gao, Peter Nemes, Huadong Pei, David W Chan, Yiliang Li, Wenge Zhu.
      The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.
    DOI:  https://doi.org/10.1038/s41419-021-03635-6
  18. Leukemia. 2021 Mar 29.
    Downregulation of MTSS1 in acute myeloid leukemia is associated with a poor prognosis, chemotherapy resistance, and disease aggressiveness.
    Alexander Michael Grandits, Chi Huu Nguyen, Angela Schlerka, Hubert Hackl, Heinz Sill, Julia Etzler, Elizabeth Heyes, Dagmar Stoiber, Florian Grebien, Gerwin Heller, Rotraud Wieser.
      Despite recent approval of targeted drugs for acute myeloid leukemia (AML) therapy, chemotherapy with cytosine arabinoside and anthracyclines remains an important pillar of treatment. Both primary and secondary resistance are frequent and associated with poor survival, yet the underlying molecular mechanisms are incompletely understood. In previous work, we identified genes deregulated between diagnosis and relapse of AML, corresponding to therapy naïve and resistant states, respectively. Among them was MTSS1, whose downregulation is known to enhance aggressiveness of solid tumors. Here we show that low MTSS1 expression at diagnosis was associated with a poor prognosis in AML. MTSS1 expression was regulated by promoter methylation, and reduced by cytosine arabinoside and the anthracycline daunorubicin. Experimental downregulation of MTSS1 affected the expression of numerous genes. It induced the DNA damage response kinase WEE1, and rendered human AML cell lines more resistant to cytosine arabinoside, daunorubicin, and other anti-cancer drugs. Mtss1 knockdown in murine MLL-AF9-driven AML substantially decreased disease latency, and increased leukemic burden and ex vivo chemotherapy resistance. In summary, low MTSS1 expression represents a novel factor contributing to disease aggressiveness, therapy resistance, and poor outcome in AML.
    DOI:  https://doi.org/10.1038/s41375-021-01224-2
  19. Cancer Discov. 2021 Apr 02.
    Cytotoxic Immune Cells Suppress Metastasis via Mechanical Sensing.
      Overexpression of some essential genes for metastasis led to cell stiffness-based immunosurveillance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-049
  20. Cancer Discov. 2021 Apr;11(4): 858-873
    Liquid Biopsy: From Discovery to Clinical Application.
    Catherine Alix-Panabières, Klaus Pantel.
      Over the past 10 years, circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) have received enormous attention as new biomarkers and subjects of translational research. Although both biomarkers are already used in numerous clinical trials, their clinical utility is still under investigation with promising first results. Clinical applications include early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Here, we propose a conceptual framework of CTC and ctDNA assays and point out current challenges of CTC and ctDNA research, which might structure this dynamic field of translational cancer research. SIGNIFICANCE: The analysis of blood for CTCs or cell-free nucleic acids called "liquid biopsy" has opened new avenues for cancer diagnostics, including early detection of tumors, improved risk assessment and staging, as well as early detection of relapse and monitoring of tumor evolution in the context of cancer therapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1311
  21. Cancer Discov. 2021 Apr;11(4): 815-821
    Emerging Trends in Cancer Drug Discovery-From Drugging the "Undruggable" to Overcoming Resistance.
    Joachim Rudolph, Jeff Settleman, Shiva Malek.
      Technology advancement and the courage to challenge dogma have been key elements that have continuously shifted druggability limits. We illustrate this notion with several recent cancer drug-discovery examples, while also giving an outlook on the opportunities offered by newer modalities such as chemically induced proximity and direct targeting of RNA. Treatment resistance is a major impediment to the goal of durable efficacy and cure, but the confluence of new biological insights, novel drug modalities, and drug combinations is predicted to enable transformative progress in this decade and beyond.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0260
  22. Mol Ther. 2021 Mar 25. pii: S1525-0016(21)00145-3. [Epub ahead of print]
    The Functional GRHL3-Filaggrin Axis Maintains a Tumour Differentiation Potential and Influences Drug Sensitivity.
    Yuchen Bai, Zixuan Zhao, Jarryd Boath, Bryce J van Denderen, Charbel Darido.
      Current therapies for treating heterogeneous cancers such as head and neck squamous cell carcinoma (HNSCC) are non-selective and are administered independent of response biomarkers. Therapy resistance subsequently emerges, resulting in increased cellular proliferation that is associated with loss of differentiation. Whether a cancer cell differentiation potential can dictate therapy responsiveness is still currently unknown. A multi-omic approach integrating whole-genome and whole-transcriptome sequencing with drug sensitivity was employed in a HNSCC mouse model, primary patients' data and human cell lines to assess the potential of functional differentiation in predicting therapy response. Interestingly, a subset of HNSCC with effective GRHL3-dependent differentiation was the most sensitive to inhibitors of PI3K/mTOR, c-MYC and STAT3 signaling. Furthermore, we identified the GRHL3-differentiation target gene Filaggrin (FLG) as a response biomarker and more importantly, stratified HNSCC subsets as treatment resistant based on their FLG mutational profile. The loss of FLG in sensitive HNSCC resulted in a dramatic resistance to targeted therapies while the GRHL3-FLG signature predicted a favourable patient prognosis. This study provides evidence for a functional GRHL3-FLG tumour-specific differentiation axis that regulates targeted therapy response in HNSCC and establishes a rationale for clinical investigation of differentiation-paired targeted therapy in heterogeneous cancers.
    Keywords:  HNSCC; biomarkers; differentiation; sensitivity; targeted therapy
    DOI:  https://doi.org/10.1016/j.ymthe.2021.03.016
  23. Cancer Discov. 2021 Apr;11(4): 810-814
    The Promising Evolution of Targeted Therapeutic Strategies in Cancer.
    Solange Peters, Tony Mok, Antonio Passaro, Pasi Antero Jänne.
      The upcoming decade of precision medicine for cancer is moving from the translation of specific genetic findings into clinically relevant improvement to the qualitative analyses of the genomic and immune tumor microenvironment, for an integrated treatment strategy in both metastatic and early disease.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0124
  24. Cancer Discov. 2021 Apr;11(4): 960-970
    Decoding Cancer Biology One Cell at a Time.
    L Nicolas Gonzalez Castro, Itay Tirosh, Mario L Suvà.
      Human tumors are composed of diverse malignant and nonmalignant cells, generating a complex ecosystem that governs tumor biology and response to treatments. Recent technological advances have enabled the characterization of tumors at single-cell resolution, providing a compelling strategy to dissect their intricate biology. Here we describe recent developments in single-cell expression profiling and the studies applying them in clinical settings. We highlight some of the powerful insights gleaned from these studies for tumor classification, stem cell programs, tumor microenvironment, metastasis, and response to targeted and immune therapies. SIGNIFICANCE: Intratumor heterogeneity (ITH) has been a major barrier to our understanding of cancer. Single-cell genomics is leading a revolution in our ability to systematically dissect ITH. In this review, we focus on single-cell expression profiling and lessons learned in key aspects of human tumor biology.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1376
  25. Cancer Cell. 2021 Mar 30. pii: S1535-6108(21)00162-8. [Epub ahead of print]
    Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver.
    Alice Bertocchi, Sara Carloni, Paola Simona Ravenda, Giovanni Bertalot, Ilaria Spadoni, Antonino Lo Cascio, Sara Gandini, Michela Lizier, Daniele Braga, Francesco Asnicar, Nicola Segata, Chris Klaver, Paola Brescia, Elio Rossi, Achille Anselmo, Silvia Guglietta, Annalisa Maroli, Paola Spaggiari, Noelia Tarazona, Andres Cervantes, Silvia Marsoni, Luca Lazzari, Maria Giovanna Jodice, Chiara Luise, Marco Erreni, Salvatore Pece, Pier Paolo Di Fiore, Giuseppe Viale, Antonino Spinelli, Chiara Pozzi, Giuseppe Penna, Maria Rescigno.
      Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases.
    Keywords:  Escherichia coli; bacteria; colorectal cancer; gut vascular barrier; inflammatory monocytes; macrophages; metastases; neutrophils; premetastatic niche; vasculature
    DOI:  https://doi.org/10.1016/j.ccell.2021.03.004
  26. Life Sci. 2021 Mar 24. pii: S0024-3205(21)00397-0. [Epub ahead of print] 119412
    E2F2 drives glioma progression via PI3K/AKT in a PFKFB4-dependent manner.
    Longzhou Zhang, Zengjin Liu, Yang Dong, Lingchang Kong.
       AIMS: The effects of PFKFB4 on glycolysis during the cancer progression has been investigated, while its role in glioma remains unclear. The present study evaluated the molecular mechanism of PFKFB4 in glycolysis of glioma progression.
    MATERIALS AND METHODS: The pan-cancer platform SangerBox was inquired to investigate the E2F2 expression in tumors. The E2F2 expression was studied by qRT-PCR and immunohistochemistry in collected glioma and normal brain tissues and by qRT-PCR and western blot in glioma cells. The relationship between the E2F2 expression in glioma tissues and patients' prognosis was analyzed. The cell malignant phenotype, glycolysis, growth and metastasis were examined by CCK-8, EdU, colony formation, flow cytometry, wound healing, Transwell assays, ELISA kits, and tumorigenesis and metastasis assays. Downstream targets of E2F2 were searched in hTFtarget, followed by pathway enrichment analysis. The expression of these targets and their correlation with E2F2 expression in gliomas were investigated through the GEPIA website. After ChIP and luciferase assays, the effect of the target on glioma was investigated.
    KEY FINDINGS: E2F2 was overexpressed in glioma patients and predicted poor prognoses. E2F2 promoted cell proliferation, colony formation, DNA synthesis, migration, invasion and glycolysis, and inhibited apoptosis. Meanwhile, inhibition of E2F2 suppressed the growth and metastasis of gliomas. E2F2 elevated the PFKFB4 expression transcriptionally by binding to its promoter and activated PI3K/AKT pathway. The promotion of glioma metastasis and glycolysis by E2F2 was mitigated by PFKFB4 knockdown.
    SIGNIFICANCE: E2F2-mediated transcriptional enhancement of PFKFB4 expression regulated the phosphorylation of PI3K/AKT to promote glioma malignancy progression.
    Keywords:  E2F2; Glioma; Glycolysis; PFKFB4; PI3K/AKT
    DOI:  https://doi.org/10.1016/j.lfs.2021.119412
  27. Clin Cancer Res. 2021 Mar 29. pii: clincanres.4048.2020. [Epub ahead of print]
    Genomic, Transcriptomic and Proteomic Profiling of Metastatic Breast Cancer.
    Argun Akcakanat, Xiaofeng Zheng, Christian X Cruz Pico, TaeBeom Kim, Ken Chen, Anil Korkut, Aysegul A Sahin, Vijaykumar R Holla, Emily Tarco, Gopal Singh, Senthilkumar Damodaran, Gordon B Mills, Ana Maria Gonzalez-Angulo, Funda Meric-Bernstam.
       BACKGROUND: Metastatic breast cancer (MBC) is not curable and there is a growing interest in personalized therapy options. Here we report molecular profiling of MBC focusing on molecular evolution in actionable alterations.
    EXPERIMENTAL DESIGN: Sixty-two patients with MBC were included. An analysis of DNA, RNA and functional proteomics was done, and matched primary and metastatic tumors were compared when feasible.
    RESULTS: Targeted exome sequencing of 41 tumors identified common alterations in TP53 (21; 51%), PIK3CA (20; 49%), as well as alterations in several emerging biomarkers such as NF1 mutations/deletions (6; 15%), PTEN mutations (4; 10%), ARID1A mutations/deletions (6; 15%). Among 27 hormone receptor-positive patients, we identified MDM2 amplifications (3; 11%), FGFR1 amplifications (5; 19%), ATM mutations (2; 7%), and ESR1 mutations (4; 15%). In 10 patients with matched primary and metastatic tumors that underwent targeted exome sequencing, discordances in actionable alterations were common, including NF1 loss in 3 patients, loss of PIK3CA mutation in 1 patient, and acquired ESR1 mutations in 3 patients. RNA-seq in matched samples confirmed loss of NF1 expression with genomic NF1 loss. Among 33 patients with matched primary and metastatic samples that underwent RNA profiling, 14 actionable genes were differentially expressed, including antibody drug conjugate targets LIV-1 and B7-H3.
    CONCLUSION: Molecular profiling in MBC reveals multiple common as well as less frequent but potentially actionable alterations. Genomic and transcriptional profiling demonstrates intertumoral heterogeneity and potential evolution of actionable targets with tumor progression. Further work is needed to optimize testing and integrated analysis for treatment selection.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4048
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