NON-COMMUNICABLE DISEASES / Cancer
Regulation of gene expression by transcription factors, role of receptor tyrosine kinases in cancer malignancies, aberrant gene expression in carcinogenesis, alterations in signal transduction pathways and gene translocations.
Description of Research
The overall goals of the Group are to utilize genomics and proteomics tools and signal transduction resources to accelerate comparative analysis of aberrant gene expression in carcinogenesis and to study alterations in signal transduction pathways during development of cancers.
Cancer Cell Survival and Apoptosis
We recently identified the two members of the GADD45 family as key players in apoptosis induction of cancer cells and inhibition of tumor formation. We demonstrated that GADD45α and GADD45γ repression plays an unambiguous and universal role in the ability of tumors to escape programmed cell death. Analysis of in vivo interacting proteins using a mass spectrometry approach identified the cdk11 p58 and a DCND1 (defective in cullin neddylation 1) as partners of the GADD45 family members.
Transcription factors and cancer
A number of transcription factors are overactive in most human cancer cells, making these good targets for the development of anticancer drugs. The epithelium-specific Ets transcription factor, PDEF, plays a role in prostate and breast cancer, although its precise function has not been established. Our studies also focus on determining the biological relevance of PDEF in prostate cancer. Current efforts are focused on understanding how the PDEF transcription factor is regulated and, more importantly, degraded.
The Role of tyrosine kinase receptors in cancer development
Our Group also focused on identification of potential therapeutic targets that are upregulated in cancer with particular emphasis on cell surface receptors. We identified several tyrosine kinase receptors whose expression was specifically increased in cancer when compared to control or other subtypes. AXL is most consistently upregulated tyrosine kinase receptor in several cancer types. Our hypothesis is that targeting the AXL tyrosine kinase will inhibit cancer growth and thus lead to a novel therapeutic entry point for cancer.
Genetics of Prostate Cancer in African men
Researchers have been investigating factors that govern the aggressive prostate cancer phenotype which is commonly found in black populations. Considering the low socioeconomic status of most African patients, a novel non-invasive and affordable marker specifically tailored towards early diagnosis and treatment monitoring is most desirable. We will perform large scale genomics and proteomics research in order to identify genes and biomarkers involved in the development of aggressive stage of the disease that is more prevalent in men with African descent.
The Group has recently discovered that the blood of African patients suffering from aggressive forms of prostate cancer has an altered metabolomic profile characterized by high levels of VLDL, indicative of bad cholesterol, and two types of protein glycosylation, indicative of the inflammatory response (Cacciatore, S., et al. Cancer Metab. 2021). This previously unknown relationship between metabolism and inflammation may be used to help prostate cancer diagnosis and stratification of the severity of the disease.
Cacciatore S, Wium M, Licari C, Masieri L, Anderson C, Salukazana AS, Kaestner L, Carini M, Carbone GM,
Catapano CV, Loda M, Libermann TA, Zerbini LF. Inflammatory metabolic profile of South African patients
with prostate cancer. Cancer & Metabolism 9:29. 2021
Elebo N, Omoshoro-Jones J, Fru PN, Devar J, De Wet van Zyl C, Vorster BC, Smith M, Cacciatore S, Zerbini LF, Candy G, and Nweke EE. Metabolic and lipoprotein profiling of Pancreatic Ductal Adenocarcinoma patients of African ancestry. Metabolites. In Press. 2021
Wium W, Ajayi-Smith A, Paccez JD, Zerbini LF. The role of the receptor tyrosine kinase Axl in carcinogenesis and development of therapeutic resistance: an overview of molecular mechanisms and future applications. Cancers. 25;13(7):1521. 2021
Albino D, Falcione M, Uboldi V, Temilola DO, Sandrini G, Merulla J, Civenni G, Kokanovic A, Stürchler A, Shinde D, Garofalo M, Mestre RP, Constâncio V, Wium M, Burrello J, Baranzini N, Grimaldi A, Theurillat JP, Bossi D, Barile L, Enrique RM, eronimo C, Zerbini LF, Catapano CV, Carbone GM. Circulating miR-424 loaded exosomes are oncogenically active in experimental models and prostate cancer patients. Communications Biology. 4:119. 2020
Zaparte A,Cappellari AR, Brandão CA, Souza JB, Borges TJ, Kist LW, Bogo MR, Zerbini LF, Pinto LF, Glaser T, Gonçalves MC, Naaldijk N, Ulrich H, Morrone FB. P2Y2 receptor activation promotes esophageal cancer cells proliferation via ERK1/2 and Akt pathways. European Journal of Pharmacology 29:173687. 2020
Semreen MH, Alniss H, El-Awady R, Cacciatore S, Mousa M, Almehdi AH, El-Huneidi W, Zerbini LF, Soares NC. GC-MS based comparative metabolomic analysis of MCF7 and MDA-MB-231 cancer cells treated with Tamoxifen and/or Paclitaxel. Journal of Proteomics 225:103875. 2020
Ojo-Okunola A, Cacciatore S, Nicol MP, du Toit E. The Determinants of the Human Milk Metabolome and Its Role in Infant Health. Metabolites10:77. 2020