Research
Nuclear signaling and cancer : V. Cavaillès

Theme 1:  Transcriptional and epigenetic regulation of cancer cell homeostasis

A. Role of protein citrullination in chromatin organization and transcriptional plasticity (P. Sharma, CRCN INSERM)

Protein citrullination is the post-translational modification of arginine to the non-coded amino acid citrulline, catalyzed by a family of enzymes called peptidyl arginine deiminases (PADIs). Among family members, PADI2 is a widely expressed isoform and an elevated level of PADI2 is associated with several cancers including breast and ovarian cancer (Beato M, Sharma P Int J Mol Sci 2020). Our recent work spotlights the PADI2-mediated citrullination of RNA polymerase II as an essential player in transcription regulation that also promotes gene transcription and cell proliferation in breast cancer cells (Sharma P et al. Mol Cell 2019). Therefore, our goal is to understand the role of arginine citrullination during cancer progression. Our main objectives will be to decipher the molecular mechanisms by which protein citrullination affects distinct stages of transcriptional events to coordinate genome dynamics and cellular processes consequently, lead to cancer progression. We will also evaluate whether specific pharmacological inhibition targeting PADI2-mediated citrullination could be a suitable therapeutic strategy for breast and ovarian cancer patients.

B. The RIP140/LCoR network in breast cancer (S Jalaguier, CRCN INSERM)

We previously characterized, at the molecular and cellular levels, the role of the RIP140/LCoR complex in breast cancer with an atypical regulation of cell proliferation (Jalaguier et al, Oncogene 2017). We evidenced a paradoxical switch in p21 expression, which paralleled an oncogenic commutation in LCoR activity. We now aim at deciphering that mechanism of action and more precisely identifying the different actors by screening a siRNA library (Collaboration with Philipp Rathert, Stuttgart). We are also precising the potential of RIP140 and LCoR as new biomarkers of gynaecological cancers (Collaboration with U Jeschke, Munich).

In collaboration with J Colinge (IRCM), we have analyzed the RIP140/LCoR transcriptome in breast cancer cells in response to estradiol and/or retinoic acid and we use system biology to modelize the nuclear receptor/transcription coregulator networks (Jimenez et al Sci Report 2021). Moreover, we have identified new pathways regulated by RIP140 and LCoR in breast cancer cells. We are now investigating how the RIP140/LCoR complex can affect these signalings in breast cancer. 

C. Regulation of nuclear signalings in intestinal inflammation (A Castet-Nicolas MCU-PH - M Lapierre CRCN INSERM - V Cavaillès DR1 CNRS)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), which is characterized by the inflammation of the colon and rectum mucosal layer and which evolves by periods of relapse and remission. Several studies have demonstrated that UC is linked to a defect of mucus production, due to the rarefaction of goblet cells. Our recent data suggest that RIP140 strongly cross-talks with the Notch pathway in colon cancer cells and regulates the differentiation of goblet cells. The role of RIP140 in intestinal permeability and inflammatory response will be investigated together with its relevance as a potential new biological marker in inflammatory bowel diseases.

Theme 2:  Molecular circuitries involved in resistance to treatments

A. Control of intestinal cancer stem cell behavior (M Lapierre, CRCN INSERM)

We previously reported that RIP140 inhibits the Wnt/βcatenin signaling and controls the differentiation, proliferation and turnover of the intestinal epithelium by regulating the expression and activity of different transcription factors (Lapierre et al J Clin Invest 2014). It is known that tumor-initiating cells or cancer stem cells (CSCs) are likely to be the cells that sustain tumor growth and account for the therapeutic refractoriness and dissemination of metastases that ultimately causes the patient death. Our unpublished data strongly support a role of RIP140 in the control of intestinal stemness. The objectives are to define the relevance of the transcription factor RIP140 in the regulation of the intestinal stem cells phenotype. To this aim, we have set up the protocol to obtain and manipulate intestinal organoids, which will be very helpful to decipher the role of RIP140 on intestinal homeostasis. In parallel, we will clarify its involvement in the control of colorectal cancer aggressiveness and response to chemotherapy.

B. Regulation of the tumor immune ecosystem in microsatellite instable colorectal cancers (A Castet-Nicolas MCU-PH - M Lapierre CRCN INSERM - V Cavaillès DR1 CNRS)

In CRCs, longer survival is associated with the level of tumor infiltrating lymphocytes at the basis of antitumor immunity. Microsatellite instability (MSI) which is linked to defective DNA mismatch repair (dMMR) is a major predictive biomarker for the efficacy of immunotherapies. Our results demonstrate that RIP40 controls MSI via the expression of MSH2/MSH6 genes and that a RIPMSI frameshift mutant is a marker of poor prognosis in MSI-dependent CRCs. Moreover, our preliminary data indicate that RIP140 expression participates in the remodeling of the tumor immune microenvironment. Our project aims to decipher, how RIP140 participates in MSI-dependent intestinal tumorigenesis and regulates tumor immune microenvironment remodeling and to determine whether RIP140 functional expression may predict the response of MSI CRC patients to immune therapies.

C. Role of RIP140 in acute myeloid leukemia (AML) (C Teyssier, CRCN INSERM)

In contrast to solid tumors, high expression of RIP140 is associated with a poor prognosis in AML. The analysis of various transcriptomic data has shown that the RIP140 gene is amplified in patients with AML with complex karyotypes and is expressed at high levels in leukemic stem cells. Our preliminary results suggest that RIP140 could play a key role in the biology of AML, in the energetic metabolism of these tumors and, consequently, in their response to treatment. Indeed, our unpublished results show that RIP140 controls cancer cell metabolism through the transcriptional regulation of glycolysis genes in solid breast tumors and such metabolic flexibility is responsible for chemoresistance in AML. Our objective is therefore to study the role of RIP140 in AML associated (or not with trisomy 21) and to decipher its role in ATRA-induced cell differentiation and in the metabolic flexibility of AML.

Theme 3: New biomaterials for the treatment of breast cancer metastasis (V Cavaillès, DR1 CNRS)

In this last axis, we are developing translational projects in collaboration with chemists from the IEMM in Montpellier and clinicians from the Montpellier CHU and ICM. Our goal is to develop new 3D scaffolds and biomaterials for the local administration of drugs for the treatment of bone metastases of breast cancers. Part of this work is developed through a partnership with the start-up Biologic4Life (Pertuis, France).