Project description:We performed single cell RNA-Seq of FACS-isolated CD45+ leukocytes and Lin-CD24- prostate stromal cells from Col1a2-TRAMP(Control) group and Col1a2-Foxf2-TRAMP group. Unsupervised clustering analysis on integrated single-cell datasets revealed an increased CD8+ T cell frequency and activity and a decreased Macrophage and MDSC activity in the Col1a2-Foxf2-TRAMP mice. The analysis in TRAMP mice revealed two major subpopulations that represented the myofibroblastic CAF (myCAF) and inflammatory CAF (iCAF). The percentage of myCAF increased by 15% in the Col1a2-Foxf2-TRAMP mice, suggesting that Foxf2 induced a shift toward the myCAF phenotype. On the other hand, the overall CAF gene signature score defined by the average expression of 30 CAF-associated genes on a single cell level was slightly but significantly reduced in the Col1a2-Foxf2-TRAMP mice.
Project description:Osteopontin (OPN) is a secreted glycoprotein, belonging to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer cells has been associated with disease progression, androgen independence and metastases. Nevertheless the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN-/-) mice and followed tumor onset and progression in these double mutants. Ultrasound examination detected the early onset of a spherical homogeneous tumor in about 60% of OPN-/- TRAMP mice that seldom occurs in parental TRAMP mice. Histology and immunohistochemistry characterized these tumors for being Tag positive but negative for AR, highly proliferative and endowed of neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus -sufficient TRAMP tumors. Down-regulated genes included key genes of TGFï?¢ pathway, and a role for TGFï?¢ in NE differentiation of prostate cancer was also confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human NE tumours. These data underscore a novel role of OPN at early stages of prostate cancer growth, protecting against the development of aggressive NE tumors. Total RNA obtained from prostate tumors from 18 and 30 weeks old TRAMP mice, compared to RNA extracted from prostate tumors and prostate tissue from Osteopontin-deleted TRAMP mice
Project description:We performed RNA-seq analysis of tumor infiltrating neutrophils from C57BL/6 mice and iNKT deficient Traj18-/- mice to understand the role of iNKT cells in affecting phenotype and functions of neutrophils in CRC. We observed that TANs from B6 animals were enriched for transcripts of chemokines and inflammation as well as of immune suppression. These data suggest that iNKT cells condition the phenotype of TANs.
Project description:Osteopontin (OPN) is a secreted glycoprotein, belonging to the non-structural extracellular matrix (ECM), and its over expression in human prostate cancer cells has been associated with disease progression, androgen independence and metastases. Nevertheless the pathophysiology of OPN in prostate tumorigenesis has never been studied. We crossed TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice with OPN deficient (OPN-/-) mice and followed tumor onset and progression in these double mutants. Ultrasound examination detected the early onset of a spherical homogeneous tumor in about 60% of OPN-/- TRAMP mice that seldom occurs in parental TRAMP mice. Histology and immunohistochemistry characterized these tumors for being Tag positive but negative for AR, highly proliferative and endowed of neuroendocrine (NE) features. Gene expression profiling showed up-regulation of genes involved in tumor progression, cell cycle and neuronal differentiation in OPN-deficient versus -sufficient TRAMP tumors. Down-regulated genes included key genes of TGF pathway, and a role for TGF in NE differentiation of prostate cancer was also confirmed at the protein level. Furthermore, NE genes and particularly those characterizing early prostatic lesions of OPN-deficient mice were found to correlate with those of human NE tumours. These data underscore a novel role of OPN at early stages of prostate cancer growth, protecting against the development of aggressive NE tumors.
Project description:In this dataset we show transcriptional profiles derived from adenocarcinoma or incipient neuroendocrine prostate cancer (NEPC) derived from TRAMP or SPARC-deficient TRAMP mice respectively. Genetic ablation of SPARC rendered prostate cancer cells to be prone to NEPC differentiation.
Project description:The incidence of prostate cancer is directly linked to age, but we still lack an adequate understanding of the prostatic aging-associated changes that facilitate carcinogenesis. In this study, we investigated possible associated factors in the aged prostate microenvironment, using an orthotopic mouse model of prostate cancer. We found that aged mice showed accelerated growth of TRAMP-C2 cells, compared with young mice. Metastatic lesions following intravenous injection were also more numerous in aged mice. TRAMP-C2 tumors from young and aged mice showed no significant differences concerning their proliferation index, apoptosis or angiogenesis. However, analysis of tumor-infiltrating immune cells by immunohistochemistry and RNA-seq gene expression revealed that aged mice present higher numbers of macrophages in normal prostatic tissue and that these are quickly polarized towards an M2 phenotype upon TRAMP-C2 cells engraftment.
Project description:Current smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor induces metastasis. To identify smoking-induced alterations in human prostate tumors, we analyzed gene and protein expression of tumors from current, past, and never smokers and observed distinct molecular alterations in current smokers. Specifically, an immune and inflammation signature was identified in prostate tumors of current smokers that was either attenuated or absent in past and never smokers. Key characteristics of this signature included augmented immunoglobulin expression by tumor-infiltrating B cells, NF-kB activation, and increased interleukin-8 in tumor and blood. In an alternate approach to characterize smoking-induced oncogenic alterations, we explored the effects of nicotine in prostate cancer cells and prostate cancer-prone TRAMP mice. These experiments showed that nicotine increases both invasiveness of human prostate cancer cells and metastasis in tumor-bearing TRAMP mice, indicating that nicotine can induce a phenotype that resembles the epidemiology of smoking-associated prostate cancer progression. In summary, we describe distinct oncogenic alterations in prostate tumors from current smokers and show that nicotine can enhance prostate cancer metastasis. TRAMP mice in five replicates received either tap water or a solution of 250 µg/ml of nicotine [nicotine tartrate salt (Sigma-Aldrich, St. Louis, MO)] in tap water
Project description:Examination of transcriptional changes associated with diet-induced obesity in tumor-infiltrating CD45+ leukocytes from syngeneic MC38 colorectal tumors.