Inflammation, cancer and cancer stem cells

Previous activities

The projects that are being developped by team#4 « Inflammation, Cancer, Cancer Stem Cells » aim at a better understanding of the pathological mechanisms that sustain human acute leukemia ; in order to identify new molecular targets or active molecules for innovative therapeutical strategies.

The research is conducted at fundamental and pre-clinical levels, backed by the use of relevant murine cancer models and by an active relationship with the Oncopediatric department at the hospital next door (Hôpital de l’Archet, CHU-Nice).

3 main axis are open :

1- studying the leukemic-reprogrammed metabolism to identify deregulated genes involved in metabolic addictions that can be used as new targets.

2- analyzing the pathologic properties of leukemic stem cells/leukemia initiating cells both at the roots of the disease and also responsible for relapse and treatment failure.

3- investigating the role of the NF-kappaB transcription factor as a support for abnormal survival, proliferation and resistance to treatments.

The first research axis is based a murine model that is representative of human T-cell Acute Lymphoblastoid Leukemia (T-ALL) or T-cell Lymphoblastoid Lymphoma (T-LL). It is generated by the deletion of the PTEN tumor suppressor, specifically in T cells (cre-lox technology, tPTEN-/- mice). Using tPTEN-/- mice, the team is studying the biochemical and genetic deregulations associated with T-cell transformation to find hits for future targeted therapies.

During transformation, cancer cells reprogram their metabolism to face the energetic challenges associated with intense abnormal cell division. Through this process, the cells develop metabolic addictions that could represent their Achille’s heels if targeted by specific drugs. Physiologically, PTEN is the unique biochemical brake to activation of the PI3K/Akt/mTORC pathway that transmits growth and proliferation signals and which is found abnormaly active at a high frequency in human leukemia. In particular, the mTORC1 branch is crucial to support growth through stimulation of lipid, nucleic acid and protein synthesis. Recently, the team has shown that the anti-diabetic drug metformin induced leukemic cell death after downregulating mTORC1 (Rosilio, 2012, 2013. Cancer Letters).

Besides, we also uncovered a strong addiction to Essential Amino Acid (EAA) visualized by the overexpression of the EAA transporter LAT1 and demonstrated that targeting LAT1 triggered a cell death response (Rosilio 2015. Leukemia). Using various bioinformatic analyses (GSEA, CMAP) of the tPTEN-/- gene expression profile (GSE39591), we are mining the transcriptomic data to identify the genes that drive leukemia and in particular those which are associated with metabolic reprogrammation. Candidate genes are then biologically evaluated through various in vitro and in vivo approaches including small animal imaging.

The second research axis concerns the study of Leukemia initiating cells (LICs). A first investigation is based on the use of a proprietary ex vivo niche-like culture system (NLCS : Griessinger, 2014. Stem Cells Transl Med) that allows the mantainance of LICs and chemo-resistant LICs from Acute Myeloid Leukemia (AML), as well as the quantification of their dynamic properties. The NLCS is used to dissect the pathological properties of LICs, to ameliorate AML patient prognosis and as a screening platform to identify LIC-targeting molecules.

In a second approach, we are studying the role of the BMI1 polycomb protein that is crucial for normal and leukemic stem cells. Through RNA interference, we have identified and are characterizing a new effector of BMI1 that is involved in regulation of autophagy to maintain the stemness state and to support acute transformation of Chronic Myeloid Leukemic cells (Mourgues, 2015. Leukemia).

In a third research axis we are dissecting the role of the NF-kappaB transcription factor in the tPTEN-/- mouse model. For this, we have generated double KO mice to either inactivate (DKO : PTEN-/-IKK2-/- and PTEN-/-RelA-/-) or constitutively activate (DKO : PTEN-/-IkBa-/-) the NF-kB pathway in vivo. We are now searching for NF-kB target genes that are involved in transformation, LIC maintainance and metabolism reprogramming.

Key words : Leukemia, Leukemia-initiating cells, self-renewal, metabolism, resistance, Cre-lox mice, PTEN, NF-kB, Bmi-1 ; signaling, transcriptomics, bioinformatics.

 

Last Publications

Benadiba J, Rosilio C, Nebout M, Heimeroth V, Neffati Z, Popa A, Mary D, Griessinger E, Imbert V, Sirvent N, Peyron JF. Iron chelation: an adjuvant therapy to target metabolism, growth and survival of murine PTEN-deficient T lymphoma and human T lymphoblastic leukemia/lymphoma. Leuk Lymphoma. 2016 Oct 13:1-13

Myasnikov AG, Kundhavai Natchiar S, Nebout M, Hazemann I, Imbert V, Khatter H, Peyron JF, Klaholz BP. Structure-function insights reveal the human ribosome as a cancer target for antibiotics. Nat Commun. 2016 Sep 26;7:12856

Team Publications