bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020–08–30
twenty papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology
  1. Oncogenic TRIM37 links chemoresistance and metastatic fate in triple-negative breast cancer.
  2. ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells.
  3. Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis.
  4. Pleiotropic mechanisms drive endocrine resistance in the three-dimensional bone microenvironment.
  5. Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer.
  6. 4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.
  7. Her2 promotes early dissemination of breast cancer by suppressing the p38-MK2-Hsp27 pathway that is targetable by Wip1 inhibition.
  8. Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.
  9. A third Notch in colorectal cancer progression and metastasis.
  10. Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling.
  11. Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications.
  12. Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer.
  13. Serum Methylmalonic Acid Mediates Aging-Related Cancer Aggressiveness.
  14. Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.
  15. Circulating tumor DNA genomics reveals potential mechanisms of resistance to BRAF-targeted therapies in BRAF-mutant metastatic non-small cell lung cancer patients.
  16. Impact of ERCC1, XPF and DNA Polymerase β Expression on Platinum Response in Patient-Derived Ovarian Cancer Xenografts.
  17. Inhibition of the MYC-regulated glutaminase metabolic axis is an effective synthetic lethal approach for treating chemoresistant cancers.
  18. Predicting distant metastasis and chemotherapy benefit in locally advanced rectal cancer.
  19. Midkine Is a Potential Therapeutic Target of Tumorigenesis, Angiogenesis, and Metastasis in Non-Small Cell Lung Cancer.
  20. Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo.
  1. Cancer Res. 2020 Aug 27. pii: canres.1459.2020. [Epub ahead of print]
    Oncogenic TRIM37 links chemoresistance and metastatic fate in triple-negative breast cancer.
    Piotr Przanowski, Song Lou, Rachisan Djiake Tihagam, Tanmoy Mondal, Caroline Conlan, Gururaj Shivange, Ilyas Saltani, Chandrajeet Singh, Kun Xing, Benjamin B Morris, Marty W Mayo, Luis Teixeira, Jacqueline Lehmann-Che, Jogender Tushir-Singh, Sanchita Bhatnagar.
      The majority of clinical deaths in TNBC patients are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. While tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforce changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using anti-folate receptor 1-conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-1459
  2. Nat Commun. 2020 Aug 26. 11(1): 4261
    ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells.
    Pedro Fuentes, Marta Sesé, Pedro J Guijarro, Marta Emperador, Sara Sánchez-Redondo, Héctor Peinado, Stefan Hümmer, Santiago Ramón Y Cajal.
      Metastasis, the spread of malignant cells from a primary tumour to distant sites, causes 90% of cancer-related deaths. The integrin ITGB3 has been previously described to play an essential role in breast cancer metastasis, but the precise mechanisms remain undefined. We have now uncovered essential and thus far unknown roles of ITGB3 in vesicle uptake. The functional requirement for ITGB3 derives from its interactions with heparan sulfate proteoglycans (HSPGs) and the process of integrin endocytosis, allowing the capture of extracellular vesicles and their endocytosis-mediated internalization. Key for the function of ITGB3 is the interaction and activation of focal adhesion kinase (FAK), which is required for endocytosis of these vesicles. Thus, ITGB3 has a central role in intracellular communication via extracellular vesicles, proposed to be critical for cancer metastasis.
    DOI:  https://doi.org/10.1038/s41467-020-18081-9
  3. Nat Cell Biol. 2020 Aug 24.
    Epigenetic silencing of the ubiquitin ligase subunit FBXL7 impairs c-SRC degradation and promotes epithelial-to-mesenchymal transition and metastasis.
    Loredana Moro, Daniele Simoneschi, Emma Kurz, Arnaldo A Arbini, Shaowen Jang, Nicoletta Guaragnella, Sergio Giannattasio, Wei Wang, Yu-An Chen, Geoffrey Pires, Andrew Dang, Elizabeth Hernandez, Payal Kapur, Ankita Mishra, Aristotelis Tsirigos, George Miller, Jer-Tsong Hsieh, Michele Pagano.
      Epigenetic plasticity is a pivotal factor that drives metastasis. Here, we show that the promoter of the gene that encodes the ubiquitin ligase subunit FBXL7 is hypermethylated in advanced prostate and pancreatic cancers, correlating with decreased FBXL7 mRNA and protein levels. Low FBXL7 mRNA levels are predictive of poor survival in patients with pancreatic and prostatic cancers. FBXL7 mediates the ubiquitylation and proteasomal degradation of active c-SRC after its phosphorylation at Ser 104. The DNA-demethylating agent decitabine recovers FBXL7 expression and limits epithelial-to-mesenchymal transition and cell invasion in a c-SRC-dependent manner. In vivo, FBXL7-depleted cancer cells form tumours with a high metastatic burden. Silencing of c-SRC or treatment with the c-SRC inhibitor dasatinib together with FBXL7 depletion prevents metastases. Furthermore, decitabine reduces metastases derived from prostate and pancreatic cancer cells in a FBXL7-dependent manner. Collectively, this research implicates FBXL7 as a metastasis-suppressor gene and suggests therapeutic strategies to counteract metastatic dissemination of pancreatic and prostatic cancer cells.
    DOI:  https://doi.org/10.1038/s41556-020-0560-6
  4. Cancer Res. 2020 Aug 28. pii: canres.0571.2020. [Epub ahead of print]
    Pleiotropic mechanisms drive endocrine resistance in the three-dimensional bone microenvironment.
    Eugen Dhimolea, Ricardo de Matos Simoes, Dhvanir Kansara, Xiang Weng, Shruti Sharma, Pallavi Awate, Zhiyi Liu, Dong Gao, Nicholas Mitsiades, Joseph H Schwab, Yu Chen, Rinath Jeselsohn, Aedín C Culhane, Myles Brown, Irene Georgakoudi, Constantine S Mitsiades.
      Although hormonal therapy (HT) inhibits the growth of hormone receptor-positive (HR+) breast (BrCa) and prostate (PrCa) cancers, HT resistance frequently develops within the complex metastatic microenvironment of the host organ (often the bone), a setting poorly recapitulated in 2D culture systems. To address this limitation, we cultured HR+ BrCa and PrCa spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSC). In 3D monocultures, antiestrogens and antiandrogens induced anoikis by abrogating anchorage-independent growth of HR+ cancer cells but exhibited only modest effects against tumor cells residing in the ECM niche. In contrast, BMSC induced hormone-independent growth of BrCa and PrCa spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of BMSC-induced hormone independence and HT resistance in anchorage-independent cells revealed distinct context-dependent mechanisms. Cocultures of ZR75-1 and LNCaP with BMSC exhibited paracrine IL-6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL-6 or JAK signaling. Paracrine IL-6/JAK/STAT3-mediated HT resistance was confirmed in patient-derived organoids cocultured with BMSC. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures but acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in a non-IL-6-dependent manner. Collectively, these data characterize the pleiotropic hormone-independent mechanisms underlying acquisition and restoration of anchorage-independent growth in HR+ tumors. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help refine treatment approaches.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-20-0571
  5. Mol Cancer. 2020 Aug 25. 19(1): 130
    Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer.
    Min Wang, Jun Liu, Yan Zhao, Ruizhi He, Xiaodong Xu, Xingjun Guo, Xu Li, Simiao Xu, Ji Miao, Jianpin Guo, Hang Zhang, Jun Gong, Feng Zhu, Rui Tian, Chengjian Shi, Feng Peng, Yechen Feng, Shuo Yu, Yu Xie, Jianxin Jiang, Min Li, Wenyi Wei, Chuan He, Renyi Qin.
       BACKGROUND: Pancreatic cancer is one of the most lethal human cancers. N6-methyladenosine (m6A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive.
    METHODS: LC/MS was used to profile m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14.
    RESULTS: We found that the m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo, via direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an m6A-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells.
    CONCLUSIONS: Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.
    Keywords:  METTL14; N6-methyladenosine; PERP; Pancreatic cancer; m6A
    DOI:  https://doi.org/10.1186/s12943-020-01249-8
  6. Proc Natl Acad Sci U S A. 2020 Aug 26. pii: 202014639. [Epub ahead of print]
    4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.
    Darren S Bryan, Melinda Stack, Katarzyna Krysztofiak, Urszula Cichoń, Dustin G Thomas, Alexandra Surcel, Eric S Schiffhauer, Michael A Beckett, Nikolai N Khodarev, Lai Xue, Elizabeth C Poli, Alexander T Pearson, Mitchell C Posner, Douglas N Robinson, Ronald S Rock, Ralph R Weichselbaum.
      Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (MYH14) to alter actin organization, inhibiting the mechanical program of metastasis. We identify NM2C as a specific therapeutic target. Pharmacological control of myosin isoforms is a promising approach to address metastatic disease, one that may be readily combined with other therapeutic strategies.
    Keywords:  4-hydroxyacetophenone; colorectal cancer; ex vivo motility; metastasis; nonmuscle myosin 2C
    DOI:  https://doi.org/10.1073/pnas.2014639117
  7. Oncogene. 2020 Aug 26.
    Her2 promotes early dissemination of breast cancer by suppressing the p38-MK2-Hsp27 pathway that is targetable by Wip1 inhibition.
    Juan Wang, Guanwen Wang, Dongmei Cheng, Shan Huang, Antao Chang, Xiaoming Tan, Qiong Wang, Shaorong Zhao, Dan Wu, Andy T Liu, Shuang Yang, Rong Xiang, Peiqing Sun.
      Cancer can metastasize from early lesions without detectable tumors. Despite extensive studies on metastasis in cancer cells from patients with detectable primary tumors, mechanisms for early metastatic dissemination are poorly understood. Her2 promotes breast cancer early dissemination by inhibiting p38, but the downstream pathway in this process was unknown. Using early lesion breast cancer models, we demonstrate that the effect of p38 suppression by Her2 on early dissemination is mediated by MK2 and heat shock protein 27 (Hsp27). The early disseminating cells in the MMTV-Her2 breast cancer model are Her2highp-p38lowp-MK2lowp-Hsp27low, which also exist in human breast carcinoma tissues. Suppression of p38 and MK2 by Her2 reduces MK2-mediated Hsp27 phosphorylation, and unphosphorylated Hsp27 binds to β-catenin and enhances its phosphorylation by Src, leading to β-catenin activation and disseminating phenotypes in early lesion breast cancer cells. Pharmacological inhibition of MK2 promotes, while inhibition of a p38 phosphatase Wip1 suppresses, early dissemination in vivo. These findings identify Her2-mediated suppression of the p38-MK2-Hsp27 pathway as a novel mechanism for cancer early dissemination, and provide a basis for new therapies targeting early metastatic dissemination in Her2+ breast cancer.
    DOI:  https://doi.org/10.1038/s41388-020-01437-2
  8. Nat Cell Biol. 2020 Aug 24.
    Cell-cell adhesion and 3D matrix confinement determine jamming transitions in breast cancer invasion.
    Olga Ilina, Pavlo G Gritsenko, Simon Syga, Jürgen Lippoldt, Caterina A M La Porta, Oleksandr Chepizhko, Steffen Grosser, Manon Vullings, Gert-Jan Bakker, Jörn Starruß, Peter Bult, Stefano Zapperi, Josef A Käs, Andreas Deutsch, Peter Friedl.
      Plasticity of cancer invasion and metastasis depends on the ability of cancer cells to switch between collective and single-cell dissemination, controlled by cadherin-mediated cell-cell junctions. In clinical samples, E-cadherin-expressing and -deficient tumours both invade collectively and metastasize equally, implicating additional mechanisms controlling cell-cell cooperation and individualization. Here, using spatially defined organotypic culture, intravital microscopy of mammary tumours in mice and in silico modelling, we identify cell density regulation by three-dimensional tissue boundaries to physically control collective movement irrespective of the composition and stability of cell-cell junctions. Deregulation of adherens junctions by downregulation of E-cadherin and p120-catenin resulted in a transition from coordinated to uncoordinated collective movement along extracellular boundaries, whereas single-cell escape depended on locally free tissue space. These results indicate that cadherins and extracellular matrix confinement cooperate to determine unjamming transitions and stepwise epithelial fluidization towards, ultimately, cell individualization.
    DOI:  https://doi.org/10.1038/s41556-020-0552-6
  9. J Exp Med. 2020 Oct 05. pii: e20201017. [Epub ahead of print]217(10):
    A third Notch in colorectal cancer progression and metastasis.
    Ute Koch, Freddy Radtke.
      In this issue of JEM, Varga et al. (https://doi.org/10.1084/jem.20191515) describe a mouse model of invasive and metastatic colorectal cancer (CRC) closely resembling the human consensus molecular subtype (CMS) 4 associated with the poorest overall survival of the four CMSs. Transcriptomic and bioinformatic analysis combined with pharmacological and genetic studies identified Notch3 as a promoter of tumor progression and metastasis. NOTCH3 expression was up-regulated in CMS4 CRC patients and associated with tumor staging, lymph node and distant metastasis. These findings feature NOTCH3 as putative therapeutic target for advanced CMS4 CRC patients.
    DOI:  https://doi.org/10.1084/jem.20201017
  10. Elife. 2020 Aug 26. pii: e57617. [Epub ahead of print]9
    Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling.
    Yingqi Liu, Lingling Li, Xiaoqing Liu, Yibo Wang, Lingxia Liu, Lu Peng, Jiayuan Liu, Lian Zhang, Guannan Wang, Hongyuan Li, Dongxu Liu, Baiqu Huang, Jun Lu, Yu Zhang.
      Arginine methyltransferase PRMT7 is associated with human breast cancer metastasis. Endosomal FAK signalling is critical for cancer cell migration. Here we identified the pivotal roles of PRMT7 in promoting endosomal FAK signalling activation during breast cancer metastasis. PRMT7 exerted its functions through binding to scaffold protein SHANK2 and catalyzing di-methylation of SHANK2 at R240. SHANK2 R240 methylation exposed ANK domain by disrupting its SPN-ANK domain blockade, promoting in co-accumulation of dynamin2, talin, FAK, cortactin with SHANK2 on endosomes. In addition, SHANK2 R240 methylation activated endosomal FAK/cortactin signals in vitro and in vivo. Consistently, all the levels of PRMT7, methylated SHANK2, FAK Y397 phosphorylation and cortactin Y421 phosphorylation were correlated with aggressive clinical breast cancer tissues. These findings characterize the PRMT7-dependent SHANK2 methylation as a key player in mediating endosomal FAK signals activation, also point to the value of SHANK2 R240 methylation as a target for breast cancer metastasis.
    Keywords:  cancer biology; cell biology; human
    DOI:  https://doi.org/10.7554/eLife.57617
  11. Oncogene. 2020 Aug 24.
    Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications.
    Qinyao Wei, Yun Qian, Jun Yu, Chi Chun Wong.
      Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.
    DOI:  https://doi.org/10.1038/s41388-020-01432-7
  12. Mol Cancer. 2020 Aug 26. 19(1): 131
    Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer.
    Mitsuro Kanda, Dai Shimizu, Koichi Sawaki, Shunsuke Nakamura, Shinichi Umeda, Takashi Miwa, Haruyoshi Tanaka, Chie Tanaka, Masamichi Hayashi, Yohei Iguchi, Suguru Yamada, Masahisa Katsuno, Yasuhiro Kodera.
       BACKGROUND: Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs).
    METHODS: Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr-/- mice, and assessed the clinical significance of NPTXR expression in GC specimens.
    RESULTS: NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr-/- mice showed no abnormalities in reproduction, development, metabolism, or motor function.
    CONCLUSIONS: NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.
    Keywords:  Antibody; Gastric cancer; Knockout mouse; Neuronal pentraxin receptor
    DOI:  https://doi.org/10.1186/s12943-020-01251-0
  13. Cancer Discov. 2020 Aug 28.
    Serum Methylmalonic Acid Mediates Aging-Related Cancer Aggressiveness.
      Methylmalonic acid (MMA) from older donors' sera promoted cancer-cell invasiveness and metastasis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-125
  14. Nat Commun. 2020 Aug 27. 11(1): 4306
    Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.
    Roy Rabbie, Naser Ansari-Pour, Oliver Cast, Doreen Lau, Francis Scott, Sarah J Welsh, Christine Parkinson, Leila Khoja, Luiza Moore, Mark Tullett, Kim Wong, Ingrid Ferreira, Julia M Martínez Gómez, Mitchell Levesque, Ferdia A Gallagher, Alejandro Jiménez-Sánchez, Laura Riva, Martin L Miller, Kieren Allinson, Peter J Campbell, Pippa Corrie, David C Wedge, David J Adams.
      Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
    DOI:  https://doi.org/10.1038/s41467-020-18060-0
  15. Clin Cancer Res. 2020 Aug 28. pii: clincanres.1037.2020. [Epub ahead of print]
    Circulating tumor DNA genomics reveals potential mechanisms of resistance to BRAF-targeted therapies in BRAF-mutant metastatic non-small cell lung cancer patients.
    Sandra Ortiz-Cuaran, Laura Mezquita, Aurélie Swalduz, Mihaela Aldea, Julien Mazieres, Camille Leonce, Cecile Jovelet, Anne Pradines, Virginie Avrillon, Washington René Chumbi Flores, Ludovic Lacroix, Yohann Loriot, Virginie Westeel, Maud Ngo-Camus, Claire Tissot, Christine Raynaud, Radj Gervais, Etienne Brain, Isabelle Monnet, Etienne Giroux Leprieur, Caroline Caramella, Celine Mahier-Aït Oukhatar, Natalie Hoog-Labouret, Frank de Kievit, Karen Howarth, Clive Morris, Emma Green, Luc Friboulet, Sylvie Chabaud, Jean-François Guichou, Maurice Perol, Benjamin Besse, Jean-Yves Blay, Pierre Saintigny, David Planchard.
       PURPOSE: The limited knowledge on the molecular profile of BRAF-mutant non-small cell lung cancer (NSCLC) patients who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of ctDNA targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of BRAF-mutant NSCLC patients.
    EXPERIMENTAL DESIGN: Prospective study of 78 advanced BRAF-mutant NSCLC patients, enrolled in 27 centers across France. Blood samples (n=208) were collected from BRAF-TT-naïve patients (n=47), non-progressive under treatment (n=115) or at disease progression (PD) to BRAF-TT (24/46 on BRAF-monotherapy; 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst®-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.
    RESULTS: BRAFV600E ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers and protein kinases were identified in 29% samples. ctDNA positivity at the first-radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% patients and included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1 and CTNNB1 Conclusions: ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF-mutant NSCLC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-1037
  16. Cancers (Basel). 2020 Aug 24. pii: E2398. [Epub ahead of print]12(9):
    Impact of ERCC1, XPF and DNA Polymerase β Expression on Platinum Response in Patient-Derived Ovarian Cancer Xenografts.
    Federica Guffanti, Maria Francesca Alvisi, Elisa Caiola, Francesca Ricci, Marcella De Maglie, Sabina Soldati, Monica Ganzinelli, Alessandra Decio, Raffaella Giavazzi, Eliana Rulli, Giovanna Damia.
      Platinum resistance is an unmet medical need in ovarian carcinoma. Molecular biomarkers to predict the response to platinum-based therapy could allow patient stratification and alternative therapeutic strategies early in clinical management. Sensitivity and resistance to platinum therapy are partially determined by the tumor's intrinsic DNA repair activities, including nucleotide excision repair (NER) and base excision repair (BER). We investigated the role of the NER proteins-ERCC1, XPF, ERCC1/XPF complex-and of the BER protein DNA polymerase β, as possible biomarkers of cisplatin (DDP) response in a platform of recently established patient-derived ovarian carcinoma xenografts (OC-PDXs). ERCC1 and DNA polymerase β protein expressions were measured by immunohistochemistry, the ERCC1/XPF foci number was detected by proximity ligation assay (PLA) and their mRNA levels by real-time PCR. We then correlated the proteins, gene expression and ERCC1/XPF complexes with OC-PDXs' response to platinum. To the best of our knowledge, this is the first investigation of the role of the ERCC1/XPF complex, detected by PLA, in relation to the response to DDP in ovarian carcinoma. None of the proteins in the BER and NER pathways studied predicted platinum activity in this panel of OC-PDXs, nor did the ERCC1/XPF foci number. These results were partially explained by the experimental evidence that the ERCC1/XPF complex increases after DDP treatment and this possibly better associates with the cancer cells' abilities to activate the NER pathway to repair platinum-induced damage than its basal level. Our findings highlight the need for DNA functional assays to predict the response to platinum-based therapy.
    Keywords:  base excision repair; biomarkers; cisplatin; nucleotide excision repair; ovarian carcinoma; patient-derived xenografts
    DOI:  https://doi.org/10.3390/cancers12092398
  17. Cancer Res. 2020 Aug 28. pii: canres.3971.2019. [Epub ahead of print]
    Inhibition of the MYC-regulated glutaminase metabolic axis is an effective synthetic lethal approach for treating chemoresistant cancers.
    Yao-An Shen, Jiaxin Hong, Ryoichi Asaka, Shiho Asaka, Fang-Chi Hsu, Yohan Suryo Rahmanto, Jin-Gyoung Jung, Yu-Wei Chen, Ting-Tai Yen, Alicja Tomaszewski, Cissy Zhang, Nabeel Attarwala, Angelo M DeMarzo, Ben Davidson, Chi-Mu Chuang, Xi Chen, Stephanie Gaillard, Anne Le, Ie-Ming Shih, Tian-Li Wang.
      Amplification and expression of the MYC oncogene in tumor cells, including ovarian cancer cells, correlates with poor responses to chemotherapy. As MYC is not directly targetable, we have analyzed molecular pathways downstream of MYC to identify potential therapeutic targets. Here we report that ovarian cancer cells overexpressing glutaminase (GLS), a MYC target and a key enzyme in glutaminolysis, are intrinsically resistant to platinum chemotherapy and are enriched in the intracellular antioxidant glutathione. Deprivation of glutamine by glutamine-withdrawal, GLS knockdown, or exposure to the GLS inhibitor CB-839 resulted in robust induction of reactive oxygen species in high GLS-expressing but not low GLS-expressing ovarian cancer cells. Treatment with CB-839 rendered GLShigh cells vulnerable to the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib and prolonged survival in tumor-bearing mice. These findings suggest that applying a combined therapy of GLS inhibitor and PARP inhibitor could effectively treat chemoresistant ovarian cancers, especially those with high expression of GLS.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-3971
  18. Nat Commun. 2020 Aug 27. 11(1): 4308
    Predicting distant metastasis and chemotherapy benefit in locally advanced rectal cancer.
    Zhenyu Liu, Xiaochun Meng, Hongmei Zhang, Zhenhui Li, Jiangang Liu, Kai Sun, Yankai Meng, Weixing Dai, Peiyi Xie, Yingying Ding, Meiyun Wang, Guoxiang Cai, Jie Tian.
      Distant metastasis (DM) is the main cause of treatment failure in locally advanced rectal cancer. Adjuvant chemotherapy is usually used for distant control. However, not all patients can benefit from adjuvant chemotherapy, and particularly, some patients may even get worse outcomes after the treatment. We develop and validate an MRI-based radiomic signature (RS) for prediction of DM within a multicenter dataset. The RS is proved to be an independent prognostic factor as it not only demonstrates good accuracy for discriminating patients into high and low risk of DM in all the four cohorts, but also outperforms clinical models. Within the stratified analysis, good chemotherapy efficacy is observed for patients with pN2 disease and low RS, whereas poor chemotherapy efficacy is detected in patients with pT1-2 or pN0 disease and high RS. The RS may help individualized treatment planning to select patients who may benefit from adjuvant chemotherapy for distant control.
    DOI:  https://doi.org/10.1038/s41467-020-18162-9
  19. Cancers (Basel). 2020 Aug 24. pii: E2402. [Epub ahead of print]12(9):
    Midkine Is a Potential Therapeutic Target of Tumorigenesis, Angiogenesis, and Metastasis in Non-Small Cell Lung Cancer.
    Dong Hoon Shin, Jeong Yeon Jo, Sun Ha Kim, Minyoung Choi, Chungyong Han, Beom K Choi, Sang Soo Kim.
      Hypoxia-inducible factors (HIFs) induced by reduced O2 availability activate the transcription of target genes encoding proteins that play important roles in communication between cancer and stromal cells. Cancer cells were incubated under hypoxic conditions: H1299, A549 (NSCLC); Hep3B, HepG2 (HCC); HCT116, CT26 (Colon cancer); MCF-7, MDAMB231 (Breast cancer); MKN1, MKN5 (Gastric cancer); U87MG, SHSY5Y (Brain cancer); and SKOV3, SNU840 (Ovary cancer). All cells expressed HIF-1α and HIF-2α mRNA and proteins. However, cell proliferation of NSCLC, breast, gastric, and brain cancer cells under hypoxia was more dependent on HIF-1α except for HCC cells where it was more dependent on HIF-2α. Among HIF-1α dependent cells H1299 was the most affected in terms of cell proliferation by HIF-1α knockdown. To examine which cytokines are secreted in NSCLC cells by HIF-1α to communicate with stromal cells, we performed a cytokine-profiling array with H1299. We screened the top 14 cytokines which were dependent on the HIF-1α expression pattern. Among them, midkine (MDK) expression was affected the most in response to HIF-1α. MDK is a heparin-binding growth factor that promotes angiogenesis and carcinogenesis. Indeed, MDK significantly increased HUVEV endothelial cell migration and neo- vascularization in chick chorioallantoic membrane assay (CAM) assay via paracrine signaling. In addition, MDK secreted from NSCLC cells interacted with Notch2 which activated the Notch signaling pathway and induced EMT, upregulated NF-κB, and increased cancer promotion. However, in response to MDK knock down, siRNA or the MDK inhibitor, iMDK treatment not only decreased MDK-induced migration and angiogenesis of endothelial cells but also abrogated the progression and metastasis of NSCLC cells in in vitro and in vivo orthotopic and spontaneous lung metastasis models. Consequently, iMDK treatment significantly increased mice survival rates compared with the control or MDK expression group. MDK plays a very important role in the progression and metastasis of NSCLC cells. Moreover, the MDK targeting strategy provides a potential therapeutic target for the treatment of MDK-expressing lung cancers.
    Keywords:  NSCLC; angiogenesi; metastasis; midkine; tumor progression
    DOI:  https://doi.org/10.3390/cancers12092402
  20. Proc Natl Acad Sci U S A. 2020 Aug 28. pii: 202009092. [Epub ahead of print]
    Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo.
    Xingkang He, Xin Yin, Jing Wu, Stina L Wickström, Yanhong Duo, Qiqiao Du, Shuhang Qin, Shuzhong Yao, Xu Jing, Kayoko Hosaka, Jieyu Wu, Lasse D Jensen, Andreas Lundqvist, Alexander I Salter, Lars Bräutigam, Wei Tao, Yuguo Chen, Rolf Kiessling, Yihai Cao.
      Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.
    Keywords:  cancer; cancer therapy; lymphocyte; metastasis; zebrafish
    DOI:  https://doi.org/10.1073/pnas.2009092117
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