Biology subjects

Colinge, J.

Publications and source records attributed to Colinge, J..

21 records · Page 2Linked to original sources

bioRxiv2019

The molecular landscape and microenvironment of salivary duct carcinoma reveal new therapeutic opportunities

Salivary duct carcinoma (SDC) is a rare and aggressive salivary gland cancer subtype with poor prognosis. The mutational landscape of SDC has been described rather exhaustively; yet, with respect to functional genomics and tumor microenvironment, little is known. In this study, transcriptomics and proteomics were combined to obtain the first characterization of the pathways deregulated in SDC. The data revealed the importance of Notch, TGB-{beta}, and interferon-{gamma} signaling. After associating computational biology, immunohistochemistry, multiplexed immunofluorescence, and digital imaging the first steps towards charting the cellular network within the microenvironment was initiated. According to immune infiltrate, two well-defined groups of tumors were observed, novel SDC immune checkpoints were discovered, and the key role played by macrophages and potentially NK cells in immunosuppression was shown. Furthermore, a clear trend between recurrence-free survival and M2 macrophage abundance was apparent. Independently, a measure of desmoplastic stromal reaction as determined by -SMA abundance, was also shown. Altogether, these many findings open new perspectives for understanding and treating SDC. Before applying an immunotherapy, classical patient stratification according to immune infiltrate should be taken into account. Moreover, the microenvironment offers new potential targets including macrophages or NK cells, or even fibroblasts or hyaluronic acid. Related therapies that have been developed against, e.g., pancreatic tumors could inspire equivalent therapy for SDC.\n\nAdditional informationO_LIFinancial support: MA (1 grant, GIRCI SOOM API-K 2016-811-DRC-AC), JC (2 grants, Fondation ARC PJA 20141201975, Labex EpiGenMed ANR 10-LABX-0012), AT (2 grants, Gunma University GIAR Research Program for Omics-Based Medical Science, Labex MabImprove ANR 10-LABX-0053 starting grant), ET (1 grant, SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553).\nC_LIO_LINo conflict of interest\nC_LIO_LI5408 words, 1 table, and 4 figures\nC_LI\n\nStatement of translational relevanceBased on the presence or absence of an immune infiltrate, two groups of SDC were identified. These have the potential to provide a rationale for therapy and clinical trial enrolment. Two novel immune checkpoints that could be targeted were also identified; namely, CTLA-4/CD86 and TIM-3/galectin-9. Both showed the important contribution that macrophages and NK cells have in immunosuppression. Treatments that induce reprogramming or elimination of these cells could be considered. Moreover, the importance of the desmoplastic stroma was stressed. The stroma acts as a physical barrier against therapy suggesting that strategies developed against pancreatic tumors could inspire SDC treatments. For SDC devoid of immune infiltrate, components of the stroma including fibroblasts or hyaluronic acid could be targeted, e.g., in combination with drugs against immune checkpoints or mutated genes. Finally, evidence that Notch and TGF-{beta} signaling are prevalent in SDC was obtained. This translates into additional therapeutic options.

cancer biology↗

bioRxiv2019

In Vivo Large Scale Mapping Of Protein Turnover In The Human Cerebrospinal Fluid

The extraction of accurate physiological parameters from clinical samples provides a unique perspective to understand disease etiology and evolution, including under therapy. We introduce a new proteomics framework to map patient proteome dynamics in vivo, either proteome wide or in large targeted panels. We applied it to ventricular cerebrospinal fluid (CSF) and could determine the turnover parameters of almost 200 proteins, whereas a handful were known previously. We covered a large number of neuron biology- and immune system-related proteins including many biomarkers and drug targets. This first large data set unraveled a significant relationship between turnover and protein origin that relates to our ability to investigate the central nervous system physiology precisely in future studies. Our data constitute a reference in CSF biology as well as a repertoire of peptides for the community to design new proteome dynamics analyses. The disclosed methods apply to other fluids or tissues provided sequential sample collection can be performed.

systems biology↗

bioRxiv2018

Distinct oncogenes drive distinct genome and epigenome alterations in human mammary epithelial cells

Gene expression differences, combined with distinct patterns of genomic rearrangements and epigenetic modifications, have laid the bases of molecular classification of breast cancer. Different molecular subtypes are thought to originate from different cell lineages in the mammary gland, but the early activation of an oncogene could also play a role. It is, however, difficult to discriminate the respective inputs of oncogene activation or cell type of origin in the natural history of the tumor. In this work, we have designed an experimental strategy aiming at determining whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. We show that initial activation of CCNE1, WNT1 and RASv12, which activate distinct oncogenic pathways, in shp53 immortalized HMECs results in different and reproducible profiles of mRNA and miRNA expression, copy number alterations (CNA) and DNA methylation modifications. Noticeably, HMECs transformed by RAS bore very specific profiles of CNAs and DNA methylation, clearly distinct from those shown by CCNE1 and WNT1 transformed HMECs.\n\nGenes impacted by CNAs and CpG methylation in the RAS and the CCNE1/WNT1 clusters showed clear differences, illustrating the activation of distinct pathways. Our data show that early activation of distinct oncogenic pathways leads to active adaptive events resulting in specific sets of CNAs and DNA methylation changes. We, thus, propose that activation of different oncogenes could have a role in reshaping the genetic landscape of breast cancer subtypes.\n\nAuthor summaryGenetic and epigenetic changes are at the center of cancer development. Breast cancer molecular subtypes are defined on differences in genetic and epigenetic profiles and it is generally assumed these subtypes originate from different cell lineages in the mammary gland. We propose that founding oncogenic mutations could also have an impact. To address this question, we designed an experimental model, based on the ectopic expression of different oncogenes in human mammary epithelial cells (HMEC), and monitored genetic and DNA methylation changes occurring at different stages of cell transformation. We show that transformation of HMEC by distinct oncogenes resulted in clearly different and reproducible patterns of genetic and DNA methylation changes. Genes whose expression was modified by either CNAs or CpG methylation were consistent with the dominant pathways activated and reflected the phenotypes in the respective models. We propose that DNA methylation and CNA changes correspond to adaptive responses to the activation of the oncogenic pathways. Our data strongly suggest that early activation of distinct oncogenic insults will not only impinge on the phenotypic characteristics of the resulting tumors, but also have a strong impact on their genomic and epigenetic landscapes.

cancer biology↗