CNRS ERL7368 - Signalisation et Transports Ioniques Membranaires « STIM »

Team description

The team “Calcium and Microenvironment of Stem Cells” (CMCS, Bruno Constantin - project leader), was formed in 2014 from members of the IPBC laboratory that decided to combine their recognized skills and expertises in physiology, cell biology, biochemistry and neurosciences to develop a joint project that tackles original research on the regulatory role of non-voltage gated calcium channels (TRP & ORAI) in the activity of healthy stem cells and tumor cells in glioma and leukemia models. Because of their ability to mobilize calcium influx in response to various microenvironmental signals, store-operated calcium channels (SOC) may play a pivotal role to accurately adapt neural stem cell activities to the niche signals, contributing thereby to tissue homeostasis. Our ongoing studies show that adult neural stem cells possess functional SOC that regulates the stem cells population and activity.

Aubin Penna: The research activity of our emerging group is dedicated to the study of the remodeling of calcium signaling pathways in tumor progression and metastasis formation. Our current projects focus on melanoma as biological model to explore and understand the roles played by calcium channels in the processes of tumor cells migration and invasion. Through established collaboration with chemists/biologists of the IC-CGO network, as well as private companies, we are also developing new ion channels inhibitors and investigating their therapeutic potential as anti-metastatic agents.

Role in the network

Task 1 Role of Ca2+ channels in cancer cell migration and in proliferation and self-renewal of cancer stem cells.

Of note, members of the team developed an expertise in analysis of cell migration phenotypes, and did publish a study in FASEB Journal describing the molecular mechanisms mobilized by BCR-ABL oncogene for promoting migration of leukemic cells (FASEB J 2013. Jan;27(1):123-34.). The team has developed studies on the molecular mechanisms controlling cell migration. P210bcr-abl, in addition to tyrosine kinase activity, strongly activates RhoA and ROCK and a differential regulation of cofilin and ADF was described with the collaboration of Pr. C. Ampe’s group in Gent University. CMCS is also the only french team bringing together the skills necessary to study the links between the BCR-ABL oncogene and Store-Operated Calcium Entry (SOCE) and on TRP and Orai channels in leukemia progenitors. The team has discovered a downregulation of SOCE in leukemic cells expressing P210bcr-abl and has recently developed aspect related to the calcium-dependent translocation of NFAT.

Although few studies reported that adult neural stem cells and glioma cells possess functional store-operated calcium channels (SOC) that regulate cell proliferation, their roles in adult neural stem cells and gliomas have yet only poorly been explored. In particular, there is a crucial lack of information on the involvement of SOC in the control of stemness and stem cells activation or quiescence, which are processes that underpin stem cells maintenance and, unfortunately for cancer stem cells, the tumor recurrence. Accordingly, our project aims at examining the regulatory roles of SOC calcium channels over neural stem cells and glioma cells activities.We analyze the molecular signature and the role of SOC in glioma cells and glioma stem cells. In our ongoing studies, we found that glioblastoma cell lines as well as human primary glioblastoma stem cells express SOC proteins and display SOCE. Our project aims now at determining the roles of these SOCE in i) cell proliferation, ii) cell survival/death and iii) stemness of glioblastoma cells and iv) in the context of resistance to temolozomide and tumor recurrence. We also try to determine the involvement of SOC in interactions between neural stem cells and glioma: the tumor niche

Aubin Penna: Our group brings to the projects its expertise on Orai/TRPV channels and skills in establishing molecular and cellular tools for ion channel studies. 

Co-coordinator of task 1 – Bruno Constantin:Role of Ca2+ and SK3 channels in cancer cell migration and survival

Co-coordinator of task 4 – Nicolas Bourmeyster : Cellular models development for drug testing

Involvement in tasks 1, 2, 4, 5, 6

 Role of Ca2+ and SK3 channels in cancer cell migration and survival : Clarify the role of Orai/TRPC channels and STIM1 in Ca2+ entry and determine the involvement of SK3 channel in the context of cell migration and survival in leukemia. - Explore the remodeling of TRP/Orai channels expression and function during cancer progression with a special emphasis on TRPV and melanoma tumor cell migration/invasion.

 Clinical relevance of Calcium channels (on human tumors) : demonstrate the contribution of these channels or signalplex as new pronostic biomarkers and to evaluate their impact on the therapeutic response or drug side-effects : Chronic myeloid leukemia (CML).

 Development of cellular models : TRPC1/4 channels models.- STIM/Orai and TRPV models.

 In vitro and in vivo validation of ion channels modulators : TRPV inhibitors

 Involvement in the development of multicentric platform to test new drugs: 2D/3D migration studies.