Matthieu Le Gallo

Université de Rennes 1 | UR1 · Oncogenesis Stress Signaling - Inserm U1242

Purpose. Triple-negative breast cancers (TNBC) account for 15% of all breast cancers but carry the worst prognosis. Because of their heterogenicity, these tumors are not all prone to targeted therapies. However, due to their high immune infiltration, targeting their immune microenvironment is of tremendous interest and is becoming the standard of c...

Purpose. Triple-negative breast cancers (TNBC) are defined as negative for hormonal receptors and human epidermal growth factor receptors 2 and account for 15% of breast cancers. TNBC carry the worst prognosis mainly because of their high proliferation index and the absence of efficient targeted therapies due to their molecular heterogeneity, even...

CD95 is a member of the TNF receptor superfamily that is ubiquitously expressed in healthy and pathological tissues. Stimulation of CD95 by its physiological ligand CD95L induces its oligomerization leading in turn to the transduction of either apoptotic or non‐apoptotic signals. CD95L can exist as both membrane‐anchored and soluble forms (sCD95L),...

IRE1α is constitutively active in several cancers and can contribute to cancer progression. Activated IRE1α cleaves XBP1 mRNA, a key step in production of the transcription factor XBP1s. In addition, IRE1α cleaves select mRNAs through regulated IRE1α-dependent decay (RIDD). Accumulating evidence implicates IRE1α in the regulation of lipid metabolis...

Cell death plays a pivotal role in the maintenance of tissue homeostasis. Key players in the controlled induction of cell death are the Death Receptors (DR). CD95 is a prototypic DR activated by its cognate ligand CD95L triggering programmed cell death. As a consequence, alterations in the CD95/CD95L pathway have been involved in several disease co...

Unfolded Protein Response (UPR) and Death Receptor (DR) signalling are cellular stress pathways frequently activated towards pro-tumoral cellular outputs in cancer. Experimental evidence has highlighted functional links between the UPR and signalling by the DR TRAIL-R1/2. Herein, we demonstrate that the UPR sensor IRE1 controls the expression of th...

This protocol describes a flow cytometry approach to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in COVID-19 positive patient sera samples without the need of specific laboratory facilities for viral infection. We developed a human cell-based system using Spike-expressing HEK293T cells that mimics membrane insertion and N-...

The epithelial-mesenchymal transition (EMT) and primary ciliogenesis induce stem cell properties in basal mammary stem cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis upon entry into intermediate EMT states by activating ciliogenes...

Background Artificial intelligence (AI) has the potential to transform our healthcare systems significantly. New AI technologies based on machine learning approaches should play a key role in clinical decision-making in the future. However, their implementation in health care settings remains limited, mostly due to a lack of robust validation proce...

SARS-CoV-2 pandemic has elicited a unique mobilization of the scientific community to develop efficient tools to understand and combat infection. Like other coronavirae, SARS-CoV-2 hijacks host cell secretory machinery to produce viral proteins that compose the nascent virions; including Spike (S), Envelope (E) and Membrane (M) proteins, the most e...

The SARS-CoV-2 pandemic has elicited a unique international mobilization of the scientific community to better understand this coronavirus and its associated disease and to develop efficient tools to combat infection. Similar to other coronavirae, SARS-CoV-2 hijacks the host cell complex secretory machinery to produce properly folded viral proteins...

The Epithelial-Mesenchymal Transition (EMT) and primary ciliogenesis induce stem cell properties in basal Mammary Stem Cells (MaSCs) to promote mammogenesis, but the underlying mechanisms remain incompletely understood. Here, we show that EMT transcription factors promote ciliogenesis at intermediate EMT transition states by activating ciliogenesis...

Uterine cancer is the 6th leading cause of cancer death amongst American women. Most uterine cancers are endometrial carcinomas (ECs), which are classified into histological subtypes including endometrioid, serous, and clear cell ECs. Somatic copy number alterations (SCNAs) are frequent in serous EC, infrequent in endometrioid ECs, and poorly defin...

Soluble CD95L (s-CD95L) is a chemoattractant for certain lymphocyte subpopulations. We examined whether this ligand is a prognostic marker for high-grade serous ovarian cancer (HGSOC) and whether it is associated with accumulation of immune cells in the tumor. Serum s-CD95L levels in 51 patients with advanced ovarian cancer were tested by ELISA. IH...

Objective: The use of novel methods to characterize living tumor cells relies on well-conceived biobanks. Herein, we raised the question of whether the composition of fresh and freeze/thawed dissociated tumor samples is comparable in terms of quantitative and qualitative profiling. Results: Breast cancer is a heterogeneous disease, encompassing...

Endometrial cancers are the most frequently diagnosed gynecological malignancy and were expected to be the seventh leading cause of cancer death among American women in 2015. The majority of endometrial cancers are of serous or endometrioid histology. Most human tumors, including endometrial tumors, are driven by the acquisition of pathogenic mutat...

Background: Uterine carcinosarcomas (UCSs) are a rare but clinically aggressive form of cancer. They are biphasic tumors consisting of both epithelial and sarcomatous components. The majority of uterine carcinosarcomas are clonal, with the carcinomatous cells undergoing metaplasia to give rise to the sarcomatous component. The objective of the cur...

Endothelial cells lining new blood vessels that develop during inflammatory disorders or cancers act as doors that either allow or block access to the tumor or inflamed organ. Recent data show that these endothelial cells in cancer tissues and inflamed tissues of lupus patients overexpress CD95L, the biological role of which is a subject of debate....

Background: The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. Methods: We conducted wh...

CD95 and its ligand CD95L play a major role in immune surveillance and homeostasis. CD95L is expressed by activated T lymphocytes and NK cells to induce apoptosis in cancer and virus-infected cells. The goal of this chapter is to describe a method used to immunoprecipitate CD95 and analyze its associated protein complex in cells stimulated with a c...

Isolated Th17 and Treg cells from two healthy donors were treated with or without 100 ng/mL cl-CD95L for 8 hr. Total RNA was extracted. Related to Figure 2.

Relative n-fold change in the quantity of transcripts significantly (p ≤ 0.05) and differentially expressed in Th17 and Treg cells either unstimulated or stimulated with cl-CD95L (100 ng/mL). Data for each experimental group (n = 2 per condition) are shown. Related to Figure 2.

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) pat...

CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) pat...

Globally, endometrial carcinoma causes about 74000 deaths annually. Endometrial carcinomas can be classified into several histological subtypes including endometrioid and serous histologies. Over the course of the past two years, a number of studies have decoded the exomes of endometrioid and serous endometrial carcinomas revealing novel somaticall...

Endometrial cancer (EC) is the 8th leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutat...

Background: Endometrial cancer is responsible for approximately 74 000 deaths annually among women worldwide. It is a heterogeneous disease comprising multiple histologic subtypes. In the US, the majority of deaths from endometrial carcinoma are attributed to the serous and endometrioid subtypes. An understanding of the fundamental genomic alterat...

Endometrial cancers (ECs) arise from the inner epithelial lining of the uterus. At diagnosis, the majority of ECs are carcinomas of endometrioid, serous, or clear cell histologies, or an admixture of at least two of these histological subtypes. Serous and clear ECs are rare at presentation but contribute disproportionately to mortality from EC. Thu...

Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromos...

RT-PCR analysis of 21 candidate human chromosomal instability genes in 7 human endometrial cancer cell lines. Gel electrophoresis of RT-PCR products confirms the expression of the 21 candidate chromosome instability genes in serous and endometrioid endometrial cancer cell lines. Positive and negative (water) PCR controls are shown. ACTB and GAPDH s...

MEFs derived from the Atad5+/m mice have molecular defects in suppression of PCNA ubiquitination. The level of PCNA ubiquitination in response to 0.01% MMS treatment was compared between wild-type and Atad5+/m MEFs. Bottom table shows the levels of PCNA and Ubiquitinated PCNA (Ub-PCNA) quantified by comparing to Histone H3. The level of Ub-PCNA qua...

Differential mRNA expression in tumors from Atad5+/m mice. (A) Results of unsupervised hierarchical clustering of two tumors from Atad5+/m animals. Red indicates increased gene expression and green indicates decreased gene expression in tumors (two right hand columns) relative to controls provided by surrounding tissues (two left hand columns). (B,...

The ATAD5-R1414X somatic mutation is heterozygous in endometrial tumor T51. (A) Sequence trace of matched germline DNA surrounding ATAD5 codon 1414 (boxed). Only the wild type sequence is detectable. (B) Sequence trace of genomic PCR products generated from macrodissected tumor tissue from T51. Both wildtype and mutant bases are detected at codon 1...

Oncoprints displaying the distribution of somatic mutations in endometrioid endometrial tumors as reported in this study (*) and elsewhere [44], [52], [53], [54]. Each blue bar represents an individual tumor (T). Nonsynonymous somatic mutations and MSI+ are indicated by the red bars. For MSH6, germline variants of unknown functional significance ar...

Immunoblots showing expression levels of the MRE11A, CHTF18 and ESCO1 proteins among a panel of 7 human endometrial cancer cell lines. Tubulin was used as a control for protein loading. (TIF)

RT-PCR primers used to assess the expression of 21 candidate human chromosomal instability genes. (XLSX)

PCR primers used to amplify 21 candidate human chromosomal instability genes within the discovery screen. (DOC)

PCR primers used to amplify and sequence CHTF18, ESCO1, and MRE11A within the validation screen. (DOC)

Oncoprint displaying patterns of somatic mutations in ESCO1, CHTF18, MRE11A, and ATAD5 in colorectal cancer, as reported by The Cancer Genome Atlas (TCGA). (Upper panel) Individual colorectal tumors are indicated by vertical gray bars. Genes (left) and nonsynonymous somatic mutations (orange bars) are indicated. (Lower panel) In colorectal cancers,...

Frequency of somatic mutations in the ESCO1 , CHTF18 , MRE11A , and ATAD5 cohesion genes in 105 endometrial tumors, according to microsatellite instability and MSH6 status. (XLSX)

Primers used to PCR amplify human ATAD5. (TIF)

Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ∼74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ∼22,000 protein-encoding genes in 13 primary...

Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyos...

Carcinoembryonic antigen (CEA) is a potential target for antigen-specific immunotherapy, as it is frequently overexpressed in human carcinomas. Moreover, an epitope derived from CEA, designated CAP1 (YLSGANLNL), has been proposed as naturally processed and presented by tumors in the human leukocyte antigen (HLA)-A*0201 context. Our aim was to fully...

Human Vgamma9Vdelta2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway-derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanis...

Genetic modification of human monocyte-derived dendritic cells (DC) with cDNA sequences encoding tumor-associated antigens (TAA) is a promising strategy for cancer immunotherapy. The present study aimed to develop a nonviral gene transfer method based on the use of the cationic lipophosphoramide reagent, KLN-5, as an alternative to the commonly use...

Vgamma9Vdelta2 T lymphocytes are reported to participate in the anti-tumor immune surveillance in human. They are known to recognize phosphoantigens and molecules expressed on cells undergoing neoplasic transformation. In this study, we investigated phenotype and anti-tumor cytotoxicity of ex vivo expanded Vgamma9Vdelta2 T cells in view of adoptive...

The poor prognosis associated with ovarian carcinoma (OVCA) is linked to the high incidence of local recurrence. There is a pressing need to identify factors that can play a role in OVCA growth and spread. Here, we focused on CD40, a member of the tumour necrosis factor (TNF) receptor superfamily with important functions in immune response. The exp...

Keratoconus (KC; MIM 148300) is a non-inflammatory corneal thinning disorder. Progressive thinning and protrusion of the cornea lead to loss of visual acuity for which the only effective treatment is corneal transplantation. The estimated prevalence of KC is 1–4 per 2000 in the general population.1 The age of onset is often at puberty, and the diso...