Biology subjects

Attignon, V.

Publications and source records attributed to Attignon, V..

3 recordsLinked to original sources

bioRxiv2024

MYC shapes ER-mitochondria calcium transfer by directly targeting ITPR1: implications for MYC-induced safeguard mechanisms and cancer

The MYC and NMYC transcription factors (TFs) play a key role in cell proliferation and are overexpressed in most cancer cells. However, in normal cells their overexpression triggers safeguard mechanisms promoting cell death and cellular senescence, which are bypassed in cancer cells. The mechanisms of action of this TF family are only partially understood. Here, we reveal that in normal cells MYC binds to the Inositol 1,4,5-Trisphosphate Receptor type 1 (ITPR1) gene and upregulates its expression, triggering an ER-mitochondria calcium (Ca2+) transfer, which is involved in MYC-induced cell death and senescence. Supporting a tumor suppressive role of MYC/ITPR1 axis, ITPR1 expression is generally decreased in cancer and reactivation of this pathway induces cancer cell death. Nevertheless, some cancer cells, generally expressing high levels of MYCN and/or MYC, also express high level of ITPR1, which correlates with high expression of BCL2, encoding an inhibitor of ITPR1. Strikingly, in high-risk MYCN-amplified neuroblastoma, ITPR1 expression is controlled by NMYC and its level correlates with worse patient survival. In these cells, blocking the interaction between BCL2 and ITPR1 induces mitochondrial Ca2+ accumulation and cell death, and decreases tumor size. Collectively these data highlight a new function of MYC factors by controlling Ca2+ signaling, which could constitute an unsuspected vulnerability for some cancer cells, including high-risk MYCN-amplified neuroblastoma cells.

cancer biology↗

bioRxiv2023

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

cancer biology↗

bioRxiv2022

Fusion-negative Rhabdomyosarcoma 3D-organoids as an innovative model to predict resistance to cell death inducers

Rhabdomyosarcoma (RMS) is the main form of soft-tissue sarcoma in children and adolescents. For 20 years, and despite international clinical trials, its cure rate has not really improved, and remains stuck at 20% in case of relapse. The definition of new effective therapeutic combinations is hampered by the lack of reliable models, which complicate the transposition of promising results obtained in pre-clinical studies into efficient solutions for young patients. Inter-patient heterogeneity, particularly in the so-called fusion-negative group (FNRMS), adds an additional level of difficulty in optimizing the clinical management of children and adolescents with RMS. Here, we describe an original 3D-organoid model derived from relapsed FNRMS and show that it finely mimics the characteristics of the original tumor, including inter- and intra-tumoral heterogeneity. Moreover, we have established the proof-of-concept of their preclinical potential by re-evaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on the exploitation of bulk and single-cell omics data.

cancer biology↗