A new Neu-a syngeneic model of spontaneously metastatic HER2-positive breast cancer.
Breast cancer
Cancer cell lines
Cancer metastasis
HER2
Mouse models
Pre-clinical models
Journal
Clinical & experimental metastasis
ISSN: 1573-7276
Titre abrégé: Clin Exp Metastasis
Pays: Netherlands
ID NLM: 8409970
Informations de publication
Date de publication:
08 May 2024
08 May 2024
Historique:
received:
11
03
2024
accepted:
21
04
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
8
5
2024
Statut:
aheadofprint
Résumé
Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.
Identifiants
pubmed: 38717519
doi: 10.1007/s10585-024-10289-z
pii: 10.1007/s10585-024-10289-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P50CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA013330
Pays : United States
Organisme : NCI NIH HHS
ID : P50CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA014089
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Sung H et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/CAAC.21660
doi: 10.3322/CAAC.21660
pubmed: 33538338
Riggio AI, Varley KE, Welm AL (2020) The lingering mysteries of metastatic recurrence in breast cancer. Br J Cancer 124(1):13–26. https://doi.org/10.1038/s41416-020-01161-4
doi: 10.1038/s41416-020-01161-4
pubmed: 33239679
pmcid: 7782773
Park MK, Lee CH, Lee H (2018) Mouse models of breast cancer in preclinical research. Lab Anim Res 34(4):160. https://doi.org/10.5625/LAR.2018.34.4.160
doi: 10.5625/LAR.2018.34.4.160
pubmed: 30671101
pmcid: 6333613
Kim IS, Baek SH (2010) Mouse models for breast cancer metastasis. Biochem Biophys Res Commun 394(3):443–447. https://doi.org/10.1016/J.BBRC.2010.03.070
doi: 10.1016/J.BBRC.2010.03.070
pubmed: 20230796
Macleod KF, Jacks T (1999) Insights into cancer from transgenic mouse models. J Pathol 187:43–60. https://doi.org/10.1002/(SICI)1096-9896(199901)187:1
doi: 10.1002/(SICI)1096-9896(199901)187:1
pubmed: 10341706
Green JE et al (2000) The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma. Oncogene 19(8):1020–1027. https://doi.org/10.1038/SJ.ONC.1203280
doi: 10.1038/SJ.ONC.1203280
pubmed: 10713685
Siegel PM, Shu W, Cardiff RD, Muller WJ, Massagué J (2003) Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc Natl Acad Sci U S A 100(14):8430. https://doi.org/10.1073/PNAS.0932636100
doi: 10.1073/PNAS.0932636100
pubmed: 12808151
pmcid: 166246
Lin SCJ et al (2004) Somatic mutation of p53 leads to estrogen receptor alpha-positive and -negative mouse mammary tumors with high frequency of metastasis. Cancer Res 64(10):3525–3532. https://doi.org/10.1158/0008-5472.CAN-03-3524
doi: 10.1158/0008-5472.CAN-03-3524
pubmed: 15150107
Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ (1992) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci 89(22):10578–10582. https://doi.org/10.1073/PNAS.89.22.10578
doi: 10.1073/PNAS.89.22.10578
pubmed: 1359541
pmcid: 50384
Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene a transgenic mouse model for metastatic disease. Mol Cell Biol 12(3):954. https://doi.org/10.1128/MCB.12.3.954
doi: 10.1128/MCB.12.3.954
pubmed: 1312220
pmcid: 369527
Fry EA, Taneja P, Inoue K (2017) Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu. Int J Cancer 140(3):495–503. https://doi.org/10.1002/IJC.30399
doi: 10.1002/IJC.30399
pubmed: 27553713
Song H et al (2008) An immunotolerant HER-2/neu transgenic mouse model of metastatic breast cancer. Clin Cancer Res 14(19):6116. https://doi.org/10.1158/1078-0432.CCR-07-4672
doi: 10.1158/1078-0432.CCR-07-4672
pubmed: 18829490
pmcid: 2570093
Reilly RT et al (2000) HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice. Cancer Res 60(13):3569–3576
pubmed: 10910070
Machiels JP et al (2001) Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61(9):3689–3697
pubmed: 11325840
Jaffee EM et al (1998) Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials. Cancer J Sci Am 4(3):194–203
pubmed: 9612602
Christmas BJ et al (2018) Entinostat converts immune-resistant breast and pancreatic cancers into checkpoint-responsive tumors by reprogramming tumor-infiltrating MDSCs. Cancer Immunol Res 6(12):1561–1577. https://doi.org/10.1158/2326-6066.CIR-18-0070
doi: 10.1158/2326-6066.CIR-18-0070
pubmed: 30341213
pmcid: 6279584
Gündüz UR, Gunaldi M, Isiksacan N, Gündüz S, Okuturlar Y, Kocoglu H (2016) A new marker for breast cancer diagnosis, human epididymis protein 4: A preliminary study. Mol Clin Oncol 5(2):355. https://doi.org/10.3892/MCO.2016.919
doi: 10.3892/MCO.2016.919
pubmed: 27446579
pmcid: 4950872
Seaman S et al (2017) Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3 Positive Tumor Cells and Tumor Vasculature. Cancer Cell 31(4):501. https://doi.org/10.1016/J.CCELL.2017.03.005
doi: 10.1016/J.CCELL.2017.03.005
pubmed: 28399408
pmcid: 5458750
Yang J et al (2009) Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA 106(10):3913–3918. https://doi.org/10.1073/PNAS.0810617106/SUPPL_FILE/0810617106SI.PDF
doi: 10.1073/PNAS.0810617106/SUPPL_FILE/0810617106SI.PDF
pubmed: 19237579
pmcid: 2656179
Berger T, Cheung CC, Elia AJ, Mak TW (2010) Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proc Natl Acad Sci USA 107(7):2995–3000. https://doi.org/10.1073/PNAS.1000101107/SUPPL_FILE/PNAS.201000101SI.PDF
doi: 10.1073/PNAS.1000101107/SUPPL_FILE/PNAS.201000101SI.PDF
pubmed: 20133630
pmcid: 2840296
Yeo SK et al (2020) Single-cell RNA-sequencing reveals distinct patterns of cell state heterogeneity in mouse models of breast cancer. Elife 9:1–24. https://doi.org/10.7554/ELIFE.58810
doi: 10.7554/ELIFE.58810
Sidiropoulos DN et al (2022) Entinostat decreases immune suppression to promote anti-tumor responses in a HER2+ breast tumor microenvironment. Cancer Immunol Res 10(5):565–669. https://doi.org/10.1158/2326-6066.CIR-21-0170
doi: 10.1158/2326-6066.CIR-21-0170
Gil Del Alcazar CR et al (2022) Insights into Immune Escape During Tumor Evolution and Response to Immunotherapy Using a Rat Model of Breast Cancer. Cancer Immunol Res 10(6):680. https://doi.org/10.1158/2326-6066.CIR-21-0804
doi: 10.1158/2326-6066.CIR-21-0804
pubmed: 35446942
pmcid: 9177779
Pinto MP, Dye WW, Jacobsen BM, Horwitz KB (2014) Malignant stroma increases luminal breast cancer cell proliferation and angiogenesis through platelet-derived growth factor signaling. BMC Cancer 14(1):735. https://doi.org/10.1186/1471-2407-14-735
doi: 10.1186/1471-2407-14-735
pubmed: 25274034
pmcid: 4190420
Jansson S et al (2018) The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence. Breast Cancer Res Treat 169(2):231. https://doi.org/10.1007/S10549-018-4664-7
doi: 10.1007/S10549-018-4664-7
pubmed: 29380207
pmcid: 5945746
Ma Y et al (2020) SOX9 Is essential for triple-negative breast cancer cell survival and metastasis. Mol Cancer Res 18(12):1825–1838. https://doi.org/10.1158/1541-7786.MCR-19-0311
doi: 10.1158/1541-7786.MCR-19-0311
pubmed: 32661114
pmcid: 7718423
Xing P et al (2016) Roles of low-density lipoprotein receptor-related protein 1 in tumors. Chin J Cancer 35(1):6. https://doi.org/10.1186/S40880-015-0064-0
doi: 10.1186/S40880-015-0064-0
pubmed: 26738504
pmcid: 4704379
Fayard B et al (2009) The serine protease inhibitor protease nexin-1 controls mammary cancer metastasis through LRP-1-mediated MMP-9 expression. Cancer Res 69(14):5690–5698. https://doi.org/10.1158/0008-5472.CAN-08-4573
doi: 10.1158/0008-5472.CAN-08-4573
pubmed: 19584287
Rappa G, Green TM, Karbanová J, Corbeil D, Lorico A (2015) Tetraspanin CD9 determines invasiveness and tumorigenicity of human breast cancer cells. Oncotarget 6(10):7970. https://doi.org/10.18632/ONCOTARGET.3419
doi: 10.18632/ONCOTARGET.3419
pubmed: 25762645
pmcid: 4480729
Yang C et al (2019) CXCL1 stimulates migration and invasion in ER-negative breast cancer cells via activation of the ERK/MMP2/9 signaling axis. Int J Oncol 55(3):684–696. https://doi.org/10.3892/IJO.2019.4840
doi: 10.3892/IJO.2019.4840
pubmed: 31322183
pmcid: 6685590
Moraes LA, Ampomah PB, Lim LHK (2018) Annexin A1 in inflammation and breast cancer: a new axis in the tumor microenvironment. Cell Adh Migr 12(5):417. https://doi.org/10.1080/19336918.2018.1486143
doi: 10.1080/19336918.2018.1486143
pubmed: 30122097
pmcid: 6363057
Baillo A, Giroux C, Ethier SP (2011) Knock-down of amphiregulin inhibits cellular invasion in inflammatory breast cancer. J Cell Physiol 226(10):2691–2701. https://doi.org/10.1002/JCP.22620
doi: 10.1002/JCP.22620
pubmed: 21302279
Yang M, Gao H, Chen P, Jia J, Wu S (2013) Knockdown of interferon-induced transmembrane protein 3 expression suppresses breast cancer cell growth and colony formation and affects the cell cycle. Oncol Rep 30(1):171–178. https://doi.org/10.3892/OR.2013.2428
doi: 10.3892/OR.2013.2428
pubmed: 23624618
Paulin D, Lilienbaum A, Kardjian S, Agbulut O, Li Z (2022) Vimentin: Regulation and pathogenesis. Biochimie 197:96–112. https://doi.org/10.1016/J.BIOCHI.2022.02.003
doi: 10.1016/J.BIOCHI.2022.02.003
pubmed: 35151830
Yu Y, Wang W, Lu W, Chen W, Shang A (2021) Inhibin β-A (INHBA) induces epithelial–mesenchymal transition and accelerates the motility of breast cancer cells by activating the TGF-β signaling pathway. Bioengineered 12(1):4681. https://doi.org/10.1080/21655979.2021.1957754
doi: 10.1080/21655979.2021.1957754
pubmed: 34346300
pmcid: 8806747
Helfman DM, Kim EJ, Lukanidin E, Grigorian M (2005) The metastasis associated protein S100A4: role in tumour progression and metastasis. Br J Cancer 92(11):1955–1958. https://doi.org/10.1038/sj.bjc.6602613
doi: 10.1038/sj.bjc.6602613
pubmed: 15900299
pmcid: 2361793
Elaimy AL et al (2018) VEGF-neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP β2-chimaerin. Sci Signal 11(528):eaao6897. https://doi.org/10.1126/SCISIGNAL.AAO6897/SUPPL_FILE/AAO6897_SM.PDF
doi: 10.1126/SCISIGNAL.AAO6897/SUPPL_FILE/AAO6897_SM.PDF
pubmed: 29717062
pmcid: 6592619
Yasuoka H et al (2009) Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression. BMC Cancer 9(1):220. https://doi.org/10.1186/1471-2407-9-220/FIGURES/4
doi: 10.1186/1471-2407-9-220/FIGURES/4
pubmed: 19580679
pmcid: 2719661
Zhang H, Fu L (2021) The role of ALDH2 in tumorigenesis and tumor progression: Targeting ALDH2 as a potential cancer treatment. Acta Pharm Sin B 11(6):1400. https://doi.org/10.1016/J.APSB.2021.02.008
doi: 10.1016/J.APSB.2021.02.008
pubmed: 34221859
pmcid: 8245805
Sundqvist A et al (2018) JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion. Nucleic Acids Res 46(3):1180. https://doi.org/10.1093/NAR/GKX1190
doi: 10.1093/NAR/GKX1190
pubmed: 29186616
Qiao Y et al (2015) AP-1-mediated chromatin looping regulates ZEB2 transcription: new insights into TNFα-induced epithelial-mesenchymal transition in triple-negative breast cancer. Oncotarget 6(10):7804–7814. https://doi.org/10.18632/ONCOTARGET.3158
doi: 10.18632/ONCOTARGET.3158
pubmed: 25762639
pmcid: 4480717
Ludyga N et al (2013) The impact of cysteine-rich intestinal protein 1 (CRIP1) in human breast cancer. Mol Cancer 12(1):28. https://doi.org/10.1186/1476-4598-12-28
doi: 10.1186/1476-4598-12-28
pubmed: 23570421
pmcid: 3666946
Kominsky SL et al (2003) Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene 22(13):2021–2033. https://doi.org/10.1038/SJ.ONC.1206199
doi: 10.1038/SJ.ONC.1206199
pubmed: 12673207
Martin TA, Jiang WG (2009) Loss of tight junction barrier function and its role in cancer metastasis. Biochim Biophys Acta (BBA)—Biomembranes 1788(4):872–891. https://doi.org/10.1016/J.BBAMEM.2008.11.005
doi: 10.1016/J.BBAMEM.2008.11.005
pubmed: 19059202
Hyun K-A et al (2016) Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer. Oncotarget 7(17):24677. https://doi.org/10.18632/ONCOTARGET.8250
doi: 10.18632/ONCOTARGET.8250
pubmed: 27013581
pmcid: 5029733
Liu F, Gu LN, Shan BE, Geng CZ, Sang MX (2016) Biomarkers for EMT and MET in breast cancer: an update. Oncol Lett 12(6):4869. https://doi.org/10.3892/OL.2016.5369
doi: 10.3892/OL.2016.5369
pubmed: 28105194
pmcid: 5228449
Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420. https://doi.org/10.1172/JCI39104
doi: 10.1172/JCI39104
pubmed: 19487818
pmcid: 2689101
Vogel CL et al (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726. https://doi.org/10.1200/JCO.20.3.719
doi: 10.1200/JCO.20.3.719
pubmed: 11821453
Roussos ET et al (2011) Mena invasive (MenaINV) and Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM. Clin Exp Metastasis 28(6):515–527. https://doi.org/10.1007/S10585-011-9388-6/FIGURES/7
doi: 10.1007/S10585-011-9388-6/FIGURES/7
pubmed: 21484349
pmcid: 3459587
Philippar U et al (2008) A mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev Cell 15(6):813. https://doi.org/10.1016/J.DEVCEL.2008.09.003
doi: 10.1016/J.DEVCEL.2008.09.003
pubmed: 19081071
pmcid: 2637261
Sharma VP et al (2021) Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination. Nat Commun 12(1):1–24. https://doi.org/10.1038/s41467-021-27308-2
doi: 10.1038/s41467-021-27308-2
Borriello L et al (2022) Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells. Nat Commun 13(1):1–19. https://doi.org/10.1038/s41467-022-28076-3
doi: 10.1038/s41467-022-28076-3
Karagiannis GS, Goswami S, Jones JG, Oktay MH, Condeelis JS (2016) Signatures of breast cancer metastasis at a glance. J Cell Sci 129(9):1751–1758. https://doi.org/10.1242/JCS.183129/-/DC2
doi: 10.1242/JCS.183129/-/DC2
pubmed: 27084578
pmcid: 4893654
Karagiannis GS et al (2017) Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med 9(397):1–15. https://doi.org/10.1126/SCITRANSLMED.AAN0026
doi: 10.1126/SCITRANSLMED.AAN0026
Ashton TM, Gillies McKenna W, Kunz-Schughart LA, Higgins GS (2018) Oxidative phosphorylation as an emerging target in cancer therapy. Clin Cancer Res 24(11):2482–2490. https://doi.org/10.1158/1078-0432.CCR-17-3070
doi: 10.1158/1078-0432.CCR-17-3070
pubmed: 29420223
Gaude E, Frezza C (2016) Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Nat Commun 7:13041. https://doi.org/10.1038/NCOMMS13041
doi: 10.1038/NCOMMS13041
pubmed: 27721378
pmcid: 5062467
Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y (2020) Molecular principles of metastasis: a hallmark of cancer revisited. Sig Transduct Target Ther 5(1):1–17. https://doi.org/10.1038/s41392-020-0134-x
doi: 10.1038/s41392-020-0134-x
Pal AK et al (2022) Metabolomics and EMT markers of breast cancer a crosstalk and future perspective. Pathophysiology 29(2):200–222. https://doi.org/10.3390/PATHOPHYSIOLOGY29020017
doi: 10.3390/PATHOPHYSIOLOGY29020017
pubmed: 35736645
pmcid: 9230911
Le Bras GF, Taubenslag KJ, Andl CD (2012) The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression. Cell Adh Migr 6(4):365. https://doi.org/10.4161/CAM.21326
doi: 10.4161/CAM.21326
pubmed: 22796940
pmcid: 3478259
Goswami S et al (2009) Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin Exp Metastasis 26(2):153. https://doi.org/10.1007/S10585-008-9225-8
doi: 10.1007/S10585-008-9225-8
pubmed: 18985426
Roussos ET et al (2011) Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J Cell Sci 124(13):2120. https://doi.org/10.1242/JCS.086231
doi: 10.1242/JCS.086231
pubmed: 21670198
pmcid: 3113666
Robinson BD et al (2009) Tumor microenvironment of metastasis in human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. Clin Cancer Res 15(7):2433. https://doi.org/10.1158/1078-0432.CCR-08-2179
doi: 10.1158/1078-0432.CCR-08-2179
pubmed: 19318480
pmcid: 3156570
Orillion A et al (2017) Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res 23(17):5187–5201. https://doi.org/10.1158/1078-0432.CCR-17-0741
doi: 10.1158/1078-0432.CCR-17-0741
pubmed: 28698201
pmcid: 5723438
Kim K et al (2014) Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 111(32):11774–11779. https://doi.org/10.1073/PNAS.1410626111/-/DCSUPPLEMENTAL
doi: 10.1073/PNAS.1410626111/-/DCSUPPLEMENTAL
pubmed: 25071169
pmcid: 4136565