Malignant transformation | EPFL Graph Search

Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor. Causes There are many causes of primary malignant transformation, or tumorigenesis. Most human cancers in the United States are caused by external factors, and these factors are largely avoidable. These factors were summarized by Doll and Peto in 1981, and were still considered to be valid in 2015. These factors are listed in the table. a Reproductive and sexual behaviors include: number of partners; age at first menstruation; zero versus one or more live births Examples of diet-related malignant transformation Diet and colon cancer Colon cancer provides one example of the mechanisms by which diet, the top factor listed in the table, is an external factor in cancer. The Western diet of African A

The role of Myc in bone metabolism

Raphaëlle Stuer

Various studies have proven the involvement of Myc in cell growth and proliferation but also cell transformation and tumorigenesis. Since regulation of cell proliferation and differentiation is mandatory in bone metabolism, we investigated the role of Myc in osteoblasts. Studies involving osteoblast specific deletion of c-Myc traced by EYFP revealed no difference in fluorescence comparing mice that have either two copies, one copy or that are lacking both copies of c-Myc under the microscope. FACS analysis of these same mice showed no significant difference in numbers of EYFP positive osteoblasts among these mice. Immunofluorescence stainings showed absence of c-Myc protein in the majority of EYFP positive cells. Studies involving osteoblast specific c-Myc and N-Myc deletion traced by EYFP were performed to analyze possible consequences of loss of both genes. Bones of newborn myc-deficient mice appeared EYFP fluorescent under the microscope. FACS analysis of myc-deficient mice demonstrated variable numbers of EYFP positive osteoblasts. However, numbers of EYFP positive osteoblasts were in the same range as numbers obtained by FACS for c-Myc deficient mice. Osteoblast specific overexpression of c-Myc was analyzed using a Tet-Off model in which human c-Myc is overexpressed. qRT-PCRs showed that markers of mid to late differentiation of osteoblasts are less expressed in mice overexpressing c-Myc compared to control mice. Since mutant mice develop osteosarcomas, the expression levels of osteoblast differentiation markers were tested by qRT-PCR. Tumors revealed to be composed of overall less differentiated osteoblasts. Using these two models we could show that myc is dispensable for osteoblasts in vivo, whereas ectopic expression of c-myc leads to severe changes in the transcription profile of osteoblasts with a specific loss of mature osteoblast markers, and to the development of osteosarcomas, which show a rather immature osteoblast phenotype

2009

Novel therapeutic strategies targeting the B-cell receptor signaling and antigen presentation pathways in non-Hodgkin lymphoma

Elena Battistello

B-cell non-Hodgkin lymphomas (B-NHLs) are a heterogeneous group of tumors deriving from the malignant transformation of B cells. The two most common B-NHL subtypes are follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), which account together for 50-60% of B-NHL cases. The standard of care for advanced or transformed FL and DLBCL is a combination of chemotherapy and the anti-CD20 antibody rituximab (R-CHOP); however, this approach is curative just in a fraction of cases. In addition, despite a good characterization of the genomic lesions present in those tumors, the available targeted therapies are limited and related to only partial responses. Thus, effective and curative treatments for B-NHLs are still missing, imposing the need for the design of new therapeutic strategies for these patients. In this thesis, I characterized the mechanisms of intrinsic and acquired resistance to targeted therapies in B-NHLs and identified novel therapeutic approaches for FL and DLBCL treatment. In the first part of this thesis, I focused on the inhibition of the B cell receptor (BCR) signaling pathway in DLBCL. The propagation of the BCR signal can be blocked using the targeted BTK inhibitor ibrutinib; however, this approach is effective only in a subgroup of DLBCL patients. In my studies, I showed that, in cells intrinsically resistant to ibrutinib, the loss of BTK is compensated by an increased dependency on the PI3K/AKT pathway downstream the BCR. In addition, I proposed to target the SRC kinases which propagate the BCR signal to both BTK and PI3K/AKT, using the new inhibitor masitinib. In cell lines and patients-derived primary samples, I showed that masitinib treatment is effective in both ibrutinib-sensitive and resistant tumors, thus suggesting it as novel therapeutic approach for a broader group of patients. In the second part of this thesis, I characterized the influence of ibrutinib and masitinib treatments on tumor heterogeneity and evolution using single-cells transcriptomics approaches. I showed that, upon long-term targeted treatments, initially sensitive tumors relapse and this is associated with changes in gene expression at the single-cell level. I then identified a set of genes that might contribute to acquired resistance to these drugs. This study will serve as starting point for a broader characterization of the effect of targeted therapies on clonal dynamics and tumor heterogeneity and for the rational design of combinatorial strategies. The last part of this thesis is focused on the characterization of cathepsin S as novel therapeutic target in FL. I showed that, in FL patients, cathepsin S over-activation by a gain-of-function mutation or by gene over-expression promotes lymphomagenesis. I found that cathepsin S has an essential role in regulating the interactions of lymphoma cells with T cells infiltrated in the tumor. Indeed, deletion of cathepsin S leads to a diversification in the repertoire of antigens presented on MHC molecules, which increases tumor immunogenicity. In pre-clinical studies, I showed that cathepsin S inhibition stimulates the activation of a potent anti-tumor immune response and enhances the therapeutic efficacy of current immunotherapies. Thus, inhibition of cathepsin S could represent a novel and promising therapeutic strategy for FL treatment. In follow-up studies, we are identifying specific cathepsin S inhibitors with potential clinical applications.

EPFL2019

Expression of human papillomavirus 16 E2 protein in Schizosaccharomyces pombe delays the initiation of mitosis

Peter Martin Beard, Nicolas Fournier, Viesturs Simanis

Infection by some types of human papillomavirus (HPV) is associated with the development of cervical cancer. Analysis of viral DNA from cervical tumours shows that the E2 gene is frequently disrupted during integration into the host cell's DNA. It has therefore been suggested that loss of E2p is an important step in malignant transformation. Expression of E2p in the fission yeast Schizosaccharomyces pombe retards the G2-M transition, by delaying activation of Cdc2p kinase. In contrast, S phase progression, and commitment to cell division in late G1 are not affected. The delay is independent of the transcriptional trans-activation function of E2p, and does not result from E2p DNA binding mimicking DNA damage. Increased expression of E2p also delays mitotic initiation in mammalian cells. S. pombe may thus provide a simple model for the analysis of E2p function.

1999