Franci C, Zhou J, Jiang Z, Modrusan Z, Good Z, Jackson E, Kouros-Mehr H.
PLoS One. 2013;8(3):e58183.
Research Oncology Department, Genentech, Inc., South San Francisco, California, United States of America.
Cancer metastases arise in part from disseminated tumor cells originating from the primary tumor and from residual disease persisting after therapy. The identification of biomarkers on micro-metastases, disseminated tumors, and residual disease may yield novel tools for early detection and treatment of these disease states prior to their development into metastases and recurrent tumors. Here we describe the molecular profiling ofdisseminated tumor cells in lungs, lung metastases, and residual tumor cells in the MMTV-PyMT breast cancer model. MMTV-PyMT mice were bred with actin-GFP mice, and focal hyperplastic lesions from pubertal MMTV-PyMT;actin-GFP mice were orthotopically transplanted into FVB/n mice to track single tumor foci. Tumor-bearing mice were treated with TAC chemotherapy (docetaxel, doxorubicin, cyclophosphamide), and residual and relapsed tumor cells were sorted and profiled by mRNA microarray analysis. Data analysis revealed enrichment of the Jak/Stat pathway, Notch pathway, and epigenetic regulators in residual tumors. Stat1 was significantly up-regulated in a DNA-damage-resistant population of residual tumorcells, and a pre-existing Stat1 sub-population was identified in untreated tumors. Tumor cells from adenomas, carcinomas, lung disseminated tumorcells, and lung metastases were also sorted from MMTV-PyMT transplant mice and profiled by mRNA microarray. Whereas disseminated tumorscells appeared similar to carcinoma cells at the mRNA level, lung metastases were genotypically very different from disseminated cells and primary tumors. Lung metastases were enriched for a number of chromatin-modifying genes and stem cell-associated genes. Histone analysis of H3K4 and H3K9 suggested that lung metastases had been reprogrammed during malignant progression. These data identify novel biomarkers of residual tumorcells and disseminated tumor cells and implicate pathways that may mediate metastasis formation and tumor relapse after therapy.
Metastases and recurrent tumors are the primary causes of morbidity and mortality for cancer patients. These disease states arise from disseminated tumor cells and residual tumor cells that survive chemotherapy, respectively. Kouros-Mehr et. al. report a novel approach to identify biomarkers and pathways linked to residual disease and metastasis formation. Using a fluorescently labeled MMTV-PyMT breast cancer model, the authors profile residual tumors that persist after chemotherapy as well as disseminated tumors cells and metastases in distant organs. They identify a number of pathways up-regulated in these disease states, including JAK/STAT, Notch, and histone methyltransferases. These genes may serve as novel biomarkers and drug targets for the detection and treatment of residual tumors and micro-metastases.
Biomarkers of Residual Disease, Disseminated Tumor Cells, and Metastases in the MMTV-PyMT Breast Cancer Model.