Our group is interested in the underlying molecular mechanisms of tumor progression in cutaneous melanoma, and performs since the mid-90#s translational research, in a close cooperation between the clinical departments of Pathology, Surgical Oncology, Dermatology, and Medical Oncology. This research is facilitated by the fact that the University Hospitals harbor a vast biobank of frozen and formalin-fixed tissue specimens, including several hundreds of frozen benign and malignant cutaneous pigment cell lesions. Since some 5 years, we have focused our research on the identification and characterization of melanoma stem cells, using a variety of approaches. We have identified in fresh melanoma specimens and in cell lines a so-called #Side Population# which delineates the subpopulation of cancer cells that efficiently effluxes potentially harmful reagents including chemotherapeutic agents by membranous ABC-pumps; we have also analyzed the effect of high-dose chemotherapy on the gene expression in (recurring) melanoma lesions; and we have characterized a novel melanoma cell type in melanoma metastases, and it#s clinical relevance, by laser microdissection, gene expression analysis and immunohistochemistry. We have recently begun to generate #melanospheres# as source of melanoma stem cells, and wish to extend this research line in the coming years.
Project
Since some 5 years, we have focused our research on the identification and characterization of melanoma stem cells, using a variety of approaches. We have identified in fresh melanoma specimens and in cell lines a so-called Side Population which delineates the subpopulation of cancer cells that efficiently effluxes potentially harmful reagents including chemotherapeutic agents by membranous ABC-pumps; we have also analyzed the effect of high-dose chemotherapy on the gene expression in (recurring) melanoma lesions; and we have characterized a novel melanoma cell type in melanoma metastases, and it#s clinical relevance, by laser microdissection, gene expression analysis and immunohistochemistry. We have recently begun to generate melanospheres as source of melanoma stem cells, and wish to extend this research line in the coming years.
The study of non-adherent melanospheres has gained attention in the melanoma community since these spheres more accurately recapitulate the phenotype observed in vivo, in patient tumors, than melanoma cell lines (even if generated from the same cell line). In addition, they show extensive in vitro self-renewal and, upon inoculation in immunodeficient mice, generate xenografts that closely resemble the parental tumor. Melanospheres express various (melanoma) stem cell markers, e.g. NANOG, KLF4, PROM1 (or CD133), CD271 (or NGFR), KDM5B (or JARID1B), ABCB5 and at least in part, aldehyde dehydrogenase activity. Addition of serum reversibly transforms the melanospheres into adherent monolayers with loss of self-renewal potential and diminished expression of stem cell markers, indicating that the phenotype-switch model (in which melanoma cells switch between a quiescent, stem cell-like and migratory status, hence the term stemness, on the one hand and a proliferative status on the other) can also be applied to melanospheres.
We wish to proceed our ongoing research into melanoma stem cells, by applying the data, obtained thus far, on melanospheres, made from fresh patient melanomas and melanoma cell lines. This PhD project will include:
· In-depth comparison of melanospheres generated from fresh primary and metastatic patient melanomas with the original tumor (morphology and gene & protein expression).
· Rigorous study of the melanospheres regulome; research will focus on transcription factors (by ChIP) and DNA methylation (by bisulphite sequencing).
· A screen of various environmental factors (chemotherapeutics, hypoxia, cytokines, etc.) on the amount and phenotype of melanospheres, and on their previously-described regulome.
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· You hold a masters degree in bioengineering sciences, biomedical sciences, pharmaceutical sciences, biochemistry, biology or similar.
· You have an interest in laboratory work with special interest in oncology and you are able to work accurately and precisely. Prior practical laboratory training is a major plus point.
· You are motivated to increase your knowledge and to learn new techniques.
· You have a team spirit, but are able to work independently, and to report and discuss the obtained results.
· You will be expected to present your data at national and international meetings and to submit your work for publication in peer-reviewed journals
· You have a good knowledge of English (written and spoken level).
Potential candidates should apply for a CSC (Chinese Scholarship Council) fellowship.
Offer
We offer:
· a PhD position in a highly motivated, interdisciplinary team of post-doctoral researchers, PhD students and technical staff.
· an individual (yet with guaranteed supervision) research project with a particular translational focus on human melanoma specimens.
· a close interaction with other cancer researchers and clinicians.
· membership to the local doctoral school and the EORTC#s YIN (young investigator#s network) to further develop your critical thinking.
· the opportunity to present your data at national and international conferences and to participate in collaborations with external research partners.
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