Low molecular weight protein tyrosine phosphatase in colorectal cancer: from the bench to product generation

• Grant number: 15/20412-7
• Support Opportunities: Research Projects - Thematic Grants
• Field of knowledge: Biological Sciences - Biochemistry - Enzymology
• Principal Investigator: Carmen Veríssima Ferreira
• Grantee: Carmen Veríssima Ferreira
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: Daniel Martins-de-Souza ; Ruy Carlos Ruver Beck ; Sheila Siqueira Andrade
• Associated scholarship(s): 18/03593-6 - Tumor-educated platelets and metastasis: relevance of LMWPTP and extracellular vesicles in Colorectal Cancer, BP.DR; 17/08119-8 - Hematogenous tumor metastasis in colon rectal cancer cells: influence of LMWPTP and 3-bromopyruvate, BP.DR

Abstract

Over the past decade, the groups led by Prof. Carmen Veríssima Ferreira and Prof. Maikel Peppelenbosch have explored signal transduction pathways in order to define the action mechanisms of antitumor candidates and for identifyng molecular targets related with the aggressiveness and resistance of tumor cells. In this context, we have investigated cell lines and biopsies of patients with prostate and colorectal tumors and identified the low molecular weight protein tyrosine phosphatase (LMWPTP) as one of indicators of aggressiveness/metastasis. CRC was choosen as model because we have stablished a set of CRC cell lines with low and high level of the LMWPTP expression. Besides, currently we are taking part in a Dutch National Programme for CRC screening, therefore, we have been built up a collection of stool samples (microRNAs). Therefore, the thematic project will address four main questions: 1) Could the high expression/activity of LMWPTP in colorectal cancer (CRC) cells control the exosomes biogenesis and composition (proteins and microRNAs)? 2) Could the high expression/activity of LMWPTP in colorectal cancer (CRC) cells influence their interaction with platelets (first stage of the hematogenous dissemination of the tumor)? If so, it could explain at least in part, the pro-metastasis action of this phosphatase; 3) Could this enzyme and/or microRNAs modulated by this enzyme be used as biomarkers (from liquid biopsy - stool samples) for diagnosis, prognosis and treatment monitoring?; 4) Could the pharmaceutical formulation containing the 3-bromopyruvate, effectively inhibiting the intracellular LMWPTP, decreasing the tumor cells-platelets aggregates and affecting the release of exosomes containing pro-metastatic factors? Therefore, we point out as the main contributions of the thematic project: a) the identification of new biomarkers that can be detected without the need of biopsy - the most widely used methods for early diagnosis of CRC are faecal occult blood testing and colonoscopy. Although these tests have improved survival rates across the CRC, the occult blood testing has low sensitivity and colonoscopy is expensive and invasive. In addition, certain foods and medications can lead to false-positive results of the occult blood test. Therefore, innovation in cheaper biomarkers and methods less invasive and more precise become highly relevant; b) the use of the LMWPTP as a target for inhibiting the first stage of hematogenous dissemination - the efficiency of the spread of tumor cells depends, in part, on their capacity to form mixed aggregates with blood cells, primarily platelets; c) the development of pharmaceutical formulation containing 3-bromopyruvate (3BP) encapsulated in exosomes derived from normal colon cells - despite the great potential of 3BP as antitumoral, it has failed in the clinical trials due to its toxic effect in erythrocytes. Therefore, pharmaceutical formulations that reduce or prevent this side effect are highly desirable. Finally, since this proposal is a technological cooperation between researchers from The Netherlands (Erasmus University of Rotterdam) and Brazil (Unicamp, Unifesp and UFRGS), we foreseen actions to add impact of the proposal for all institutions involved: to organize two meetings for following up the progress of the project; to provide training for the members of involved groups and to find new partners to increase the number and diversity of patient samples. (AU)

Scientific publications

(14)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ROCHA-BRITO, KARIN J. P.; CLERICI, STEFANO PIATTO; CORDEIRO, HELON GUIMARAES; SCOTA FERREIRA, AMANDA PETRINA; BARRETO FONSECA, EMANUELLA MARIA; GONCALVES, PAOLA R.; ABRANTES, JULIA LAURA F.; MILANI, RENATO; MASSARO, RENATO RAMOS; MARIA-ENGLER, SILVYA STUCHI; et al. uercetin increases mitochondrial proteins (VDAC and SDH) and downmodulates AXL and PIM-1 tyrosine kinase receptors in NRAS melanoma cell. Biological Chemistry, v. 403, n. 3, DEC 2021. (17/04926-6, 18/03593-6, 15/20412-7)

FARIA, ALESSANDRA V. S.; ANDRADE, SHEILA S.; REIJM, AGNES N.; SPAANDER, MANON C. W.; DE MAAT, MONIEK P. M.; PEPPELENBOSCH, MAIKEL P.; FERREIRA-HALDER, V, CARMEN; FUHLER, GWENNY M.. Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients. JOURNAL OF CLINICAL MEDICINE, v. 8, n. 7, JUL 2019. (17/08119-8, 18/00736-0, 15/20412-7)

FERREIRA-HALDER, CARMEN VERISSIMA; DE SOUSA FARIA, ALESSANDRA VALERIA; ANDRADE, SHEILA SIQUEIRA. Action and function of Faecalibacterium prausnitzii in health and disease. BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY, v. 31, n. 6, p. 643-648, DEC 2017. (15/20412-7, 16/14459-3)

FARIA, ALESSANDRA V. S.; YU, BINGTING; MOMMERSTEEG, MICHIEL; DE SOUZA-OLIVEIRA, PATRICIA F.; ANDRADE, SHEILA S.; SPAANDER, MANON C. W.; DE MAAT, MONIEK P. M.; PEPPELENBOSCH, MAIKEL P.; FERREIRA-HALDER, V, CARMEN; FUHLER, GWENNY M.. Platelet-dependent signaling and Low Molecular Weight Protein Tyrosine Phosphatase expression promote aggressive phenotypic changes in gastrointestinal cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1868, n. 1, JAN 1 2022. (17/26317-1, 18/00736-0, 16/14459-3, 17/08119-8, 15/20412-7)

FARIA, ALESSANDRA V. S.; ANDRADE, SHEILA S.; PEPPELENBOSCH, MAIKEL P.; FERREIRA-HALDER, CARMEN V.; FUHLER, GWENNY M.. Platelets in aging and cancer-"double-edged sword". CANCER AND METASTASIS REVIEWS, v. 39, n. 4, p. 17-pg., 2020-09-01. (16/14459-3, 17/08119-8, 18/00736-0, 17/26317-1, 15/20412-7)

CLERICI, STEFANO PIATTO; DE SOUZA OLIVEIRA, PATRICIA FERNANDES; AKAGI, ERICA MIE; CORDEIRO, HELON GUIMARAES; AZEVEDO-MARTINS, JORDANA MARIA; DE SOUSA FARIA, ALESSANDRA VALERIA; FERREIRA-HALDER, CARMEN VERISSIMA. A comprehensive review on the role of protein tyrosine phosphatases in gastric cancer development and progression. Biological Chemistry, v. 402, n. 6, p. 663-674, MAY 2021. (17/08119-8, 17/16625-0, 15/20412-7, 18/03593-6)

FARIA, ALESSANDRA V. S.; FONSECA, EMANUELLA M. B.; FERNANDES-OLIVEIRA, PATRICIA DE S.; DE LIMA, TANES I.; CLERICI, STEFANO P.; JUSTO, GISELLE Z.; SILVEIRA, LEONARDO R.; DURAN, NELSON; FERREIRA-HALDER, CARMEN, V. Violacein switches off low molecular weight tyrosine phosphatase and rewires mitochondria in colorectal cancer cells. BIOORGANIC CHEMISTRY, v. 127, p. 9-pg., 2022-07-16. (17/08119-8, 20/04409-4, 15/20412-7, 15/11433-0, 18/03593-6)

ANDRADE, SHEILA SIQUEIRA; DE SOUSA FARIA, ALESSANDRA VALERIA; GIRAO, MANOEL JOAO BATISTA C.; FUHLER, GWENNY M.; PEPPELENBOSCH, MAIKEL P.; FERREIRA-HALDER, CARMEN, V. Biotech-Educated Platelets: Beyond Tissue Regeneration 2.0. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 17, p. 14-pg., 2020-09-01. (15/20412-7, 16/14459-3, 17/26317-1)

CORDEIRO, HELON GUIMARAES; DE SOUSA FARIA, ALESSANDRA VALERIA; FERREIRA-HALDER, CARMEN VERISSIMA. Vemurafenib downmodulates aggressiveness mediators of colorectal cancer (CRC): Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP), Protein Tyrosine Phosphatase 1B (PTP1B) and Transforming Growth Factor ss (TGF ss). Biological Chemistry, v. 401, n. 9, p. 1063-1069, AUG 2020. (17/08119-8, 15/20412-7)

FARIA, ALESSANDRA V. S.; ANDRADE, SHEILA S.; PEPPELENBOSCH, MAIKEL P.; FERREIRA-HALDER, CARMEN V.; FUHLER, GWENNY M.. Platelets in aging and cancer-{''}double-edged sword{''}. CANCER AND METASTASIS REVIEWS, v. 39, n. 4, SI, SEP 2020. (17/08119-8, 17/26317-1, 16/14459-3, 15/20412-7, 18/00736-0)

CLERICI, STEFANO PIATTO; PEPPELENBOSCH, MAIKEL; FUHLER, GWENNY; CONSONNI, SILVIO ROBERTO; FERREIRA-HALDER, CARMEN VERISSIMA. Colorectal Cancer Cell-Derived Small Extracellular Vesicles Educate Human Fibroblasts to Stimulate Migratory Capacity. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 9, JUL 15 2021. (15/20412-7, 18/03593-6)

FARIA, ALESSANDRA V. S.; CLERICI, STEFANO P.; DE SOUZA OLIVEIRA, PATRICIA F.; QUEIROZ, KARLA C. S.; PEPPELENBOSCH, MAIKEL P.; FERREIRA-HALDER, CARMEN V.. LMWPTP modulates the antioxidant response and autophagy process in human chronic myeloid leukemia cells. Molecular and Cellular Biochemistry, v. 466, n. 1-2, p. 83-89, MAR 2020. (18/03593-6, 17/08119-8, 15/20412-7)

FARIA, ALESSANDRA V. S.; ANDRADE, SHEILA S.; PEPPELENBOSCH, MAIKEL P.; FERREIRA-HALDER, V, CARMEN; FUHLER, GWENNY M.. The role of phospho-tyrosine signaling in platelet biology and hemostasis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1868, n. 3, MAR 2021. (15/20412-7, 17/26317-1, 17/08119-8, 16/14459-3, 18/00736-0)

CORDEIRO, HELON GUIMARAES; DE SOUSA FARIA, ALESSANDRA VALERIA; FERREIRA-HALDER, CARMEN VERISSIMA. Vemurafenib downmodulates aggressiveness mediators of colorectal cancer (CRC): Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP), Protein Tyrosine Phosphatase 1B (PTP1B) and Transforming Growth Factor ß (TGFß). Biological Chemistry, v. 401, n. 9, p. 7-pg., 2020-08-01. (15/20412-7, 17/08119-8)