RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

[1]  P. Kehrli,et al.  [Epidemiology of brain metastases]. , 1999, Neuro-Chirurgie.

[2]  J. Clarhaut,et al.  Serotonin and cancer: what is the link? , 2015, Current molecular medicine.

[3]  Gary K. Schwartz,et al.  Tumour exosome integrins determine organotropic metastasis , 2015, Nature.

[4]  Yusuke Nakamura,et al.  Expression profiles of metastatic brain tumor from lung adenocarcinomas on cDNA microarray. , 2006, International journal of oncology.

[5]  H. Woo,et al.  Cross-species hybridization of microarrays for studying tumor transcriptome of brain metastasis , 2011, Proceedings of the National Academy of Sciences.

[6]  J. Pearson,et al.  Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance , 2015, The Journal of pathology.

[7]  Wei Shi,et al.  featureCounts: an efficient general purpose program for assigning sequence reads to genomic features , 2013, Bioinform..

[8]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[9]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[10]  B. Fox,et al.  OX40 is a potent immune-stimulating target in late-stage cancer patients. , 2013, Cancer research.

[11]  H. Saya,et al.  Expression of CD24 is associated with HER2 expression and supports HER2-Akt signaling in HER2-positive breast cancer cells , 2014, Cancer science.

[12]  Hiroshi Tanaka,et al.  Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell , 2012, Nature Communications.

[13]  T. Maniatis,et al.  An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex , 2014, The Journal of Neuroscience.

[14]  M. Mancino,et al.  The neuronal influence on tumor progression. , 2011, Biochimica et biophysica acta.

[15]  Howard Y. Chang,et al.  Anatomic Demarcation of Cells: Genes to Patterns , 2009, Science.

[16]  T. Mcclanahan,et al.  Involvement of chemokine receptors in breast cancer metastasis , 2001, Nature.

[17]  R. Linding,et al.  The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase , 2015, Nature.

[18]  A. Buckley,et al.  Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival , 2009, Breast Cancer Research.

[19]  M. Malkin,et al.  The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma , 2004, Cancer.

[20]  M. Poot,et al.  Protein tyrosine phosphatase RQ is a phosphatidylinositol phosphatase that can regulate cell survival and proliferation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G. Mills,et al.  Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy. , 2010, Neoplasia.

[22]  W. Gerald,et al.  Genes that mediate breast cancer metastasis to the brain , 2009, Nature.

[23]  Jeremy Wazny,et al.  Xenome—a tool for classifying reads from xenograft samples , 2012, Bioinform..

[24]  I. Osman,et al.  In vivo Modeling and Molecular Characterization: A Path Toward Targeted Therapy of Melanoma Brain Metastasis , 2013, Front. Oncol..

[25]  T. Sotnikova,et al.  Tryptophan Hydroxylase-2 Controls Brain Serotonin Synthesis , 2004, Science.

[26]  I. Fidler.  The Biology of Brain Metastasis: Challenges for Therapy , 2015, Cancer journal.

[27]  Cimona V Hinton,et al.  Role of the CXCR4/CXCL12 signaling axis in breast cancer metastasis to the brain , 2010, Clinical & Experimental Metastasis.

[28]  J. Massagué,et al.  Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer , 2016, Nature.

[29]  J. Massagué,et al.  Macrophage binding to receptor VCAM-1 transmits survival signals in breast cancer cells that invade the lungs. , 2011, Cancer cell.

[30]  R. Pulido,et al.  PTPs emerge as PIPs: protein tyrosine phosphatases with lipid-phosphatase activities in human disease. , 2013, Human molecular genetics.

[31]  S. Chmura,et al.  Treatment of Brain Metastases , 2014, Oncology.

[32]  J. Massagué,et al.  Surviving at a Distance: Organ-Specific Metastasis. , 2015, Trends in cancer.

[33]  A. Herbet,et al.  Subcommissural organ/Reissner's fiber complex: Characterization of SCO‐spondin, a glycoprotein with potent activity on neurite outgrowth , 2000, Glia.

[34]  P. Steeg,et al.  Targeting metastasis , 2016, Nature Reviews Cancer.

[35]  Michael Bader,et al.  Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform , 2003, Science.

[36]  J. Massagué,et al.  Metastatic colonization by circulating tumour cells , 2016, Nature.

[37]  J. Lytton.  REVIEW ARTICLE Na + /Ca 2+ exchangers: three mammalian gene families control Ca 2+ transport , 2007 .

[38]  Lingyun Zhu,et al.  Molecular cloning of the cDNA for the catalytic subunit of human DNA polymerase δ , 1992 .

[39]  J. Massagué,et al.  Molecular Pathways Molecular Pathways : VCAM-1 as a Potential Therapeutic Target in Metastasis , 2012 .

[40]  B. Wold,et al.  Gene expression changes in a tumor xenograft by a pyrrole-imidazole polyamide , 2012, Proceedings of the National Academy of Sciences.

[41]  Steven N. Kalkanis,et al.  Current approaches to the treatment of metastatic brain tumours , 2014, Nature Reviews Clinical Oncology.

[42]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[43]  J. Lytton.  Na+/Ca2+ exchangers: three mammalian gene families control Ca2+ transport. , 2007, The Biochemical journal.

[44]  G. Lal,et al.  Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity , 2015, Front. Immunol..

[45]  J. Syväoja,et al.  Molecular cloning of the cDNA for the catalytic subunit of human DNA polymerase epsilon. , 1993, The Journal of biological chemistry.

[46]  Drew M. Pardoll,et al.  The blockade of immune checkpoints in cancer immunotherapy , 2012, Nature Reviews Cancer.

[47]  L. Zitvogel,et al.  Rationale for anti-OX40 cancer immunotherapy. , 2016, European journal of cancer.

[48]  Yusuke Yoshioka,et al.  Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier , 2015, Nature Communications.

[49]  Stephen T. C. Wong,et al.  The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells. , 2015, Cancer cell.

[50]  O. Bizzozero,et al.  Presence of the Plasma Membrane Proteolipid (Plasmolipin) in Myelin , 1990, Journal of neurochemistry.

[51]  J. Lemaire,et al.  SCO-Spondin Derived Peptide NX210 Induces Neuroprotection In Vitro and Promotes Fiber Regrowth and Functional Recovery after Spinal Cord Injury , 2014, PloS one.

[52]  H. Okano,et al.  Long-Term Safety Issues of iPSC-Based Cell Therapy in a Spinal Cord Injury Model: Oncogenic Transformation with Epithelial-Mesenchymal Transition , 2015, Stem cell reports.

[53]  Gary D. Bader,et al.  The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function , 2010, Nucleic Acids Res..

[54]  M. Kris,et al.  High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carcinoma after response to gefitinib , 2005, Cancer.

[55]  H. Saya,et al.  Periostin Is a Key Niche Component for Wound Metastasis of Melanoma , 2015, PloS one.

[56]  Yibin Kang,et al.  Bone metastasis and the metastatic niche , 2015, Journal of Molecular Medicine.

[57]  G. Hu,et al.  New horizons in tumor microenvironment biology: challenges and opportunities , 2015, BMC Medicine.

[58]  Andy J. Minn,et al.  Genes that mediate breast cancer metastasis to lung , 2005, Nature.

[59]  M. Kris,et al.  Serpins Promote Cancer Cell Survival and Vascular Co-Option in Brain Metastasis , 2014, Cell.

[60]  A. Meiniel,et al.  SCO‐spondin, a glycoprotein of the subcommissural organ/reissner's fiber complex: Evidence of a potent activity on neuronal development in primary cell cultures , 2001, Microscopy research and technique.

[61]  A. Weinberg,et al.  The role of OX40-mediated co-stimulation in T-cell activation and survival. , 2009, Critical reviews in immunology.

[62]  Jian Zhang,et al.  CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression , 2010, Cancer and Metastasis Reviews.