Early stability and late random tumor progression of a HER2-positive primary breast cancer patient-derived xenograft.

Autor: Landuzzi L; Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy., Palladini A; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Ceccarelli C; Laboratory of Oncologic Immunocytopathology, DIMES, St. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy., Asioli S; Department of Biomedical and Neuromotor Sciences, University of Bologna, Unit of Anatomic Pathology 'M. Malpighi', Bellaria Hospital, Via Altura, 3, 40139, Bologna, Italy., Nicoletti G; Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy., Giusti V; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Ruzzi F; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Ianzano ML; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Scalambra L; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Laranga R; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Balboni T; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Arigoni M; Department of Molecular Biotechnology and Health Science, University of Torino, Turin, Italy., Olivero M; Department of Oncology, University of Torino, Turin, Italy.; Candiolo Cancer Institute-FPO, IRCCS, Candiolo, 10060, Turin, Italy., Calogero RA; Department of Molecular Biotechnology and Health Science, University of Torino, Turin, Italy., De Giovanni C; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Dall'Ora M; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Di Oto E; Department of Biomedical and Neuromotor Sciences, University of Bologna, Unit of Anatomic Pathology 'M. Malpighi', Bellaria Hospital, Via Altura, 3, 40139, Bologna, Italy., Santini D; Pathology Unit, St. Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy., Foschini MP; Department of Biomedical and Neuromotor Sciences, University of Bologna, Unit of Anatomic Pathology 'M. Malpighi', Bellaria Hospital, Via Altura, 3, 40139, Bologna, Italy., Cucchi MC; Unit of Breast Surgery, Bellaria Hospital, AUSL Bologna, Bologna, Italy., Zanotti S; Department of Medical and Surgical Science, Bologna University-Breast Unit Sant'Orsola Hospital, Bologna, Italy., Taffurelli M; Department of Medical and Surgical Science, Bologna University-Breast Unit Sant'Orsola Hospital, Bologna, Italy., Nanni P; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy., Lollini PL; Laboratory of Immunology and Biology of Metastasis, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Viale Filopanti 22, 40126, Bologna, Italy. pierluigi.lollini@unibo.it.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Jan 15; Vol. 11 (1), pp. 1563. Date of Electronic Publication: 2021 Jan 15.
DOI: 10.1038/s41598-021-81085-y
Abstrakt: We established patient-derived xenografts (PDX) from human primary breast cancers and studied whether stability or progressive events occurred during long-term in vivo passages (up to 4 years) in severely immunodeficient mice. While most PDX showed stable biomarker expression and growth phenotype, a HER2-positive PDX (PDX-BRB4) originated a subline (out of 6 studied in parallel) that progressively acquired a significantly increased tumor growth rate, resistance to cell senescence of in vitro cultures, increased stem cell marker expression and high lung metastatic ability, along with a strong decrease of BCL2 expression. RNAseq analysis of the progressed subline showed that BCL2 was connected to three main hub genes also down-regulated (CDKN2A, STAT5A and WT1). Gene expression of progressed subline suggested a partial epithelial-to-mesenchymal transition. PDX-BRB4 with its progressed subline is a preclinical model mirroring the clinical paradox of high level-BCL2 as a good prognostic factor in breast cancer. Sequential in vivo passages of PDX-BRB4 chronically treated with trastuzumab developed progressive loss of sensitivity to trastuzumab while HER2 expression and sensitivity to the pan-HER tyrosine kinase inhibitor neratinib were maintained. Long-term PDX studies, even though demanding, can originate new preclinical models, suitable to investigate the mechanisms of breast cancer progression and new therapeutic approaches.
Databáze: MEDLINE
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