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The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in the pathogenesis of colorectal carcinoma

English title The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in the pathogenesis of colorectal carcinoma
Applicant Scharl Michael
Number 184753
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Gastroenterologie und Hepatologie Departement Innere Medizin Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Cancer Research
Start/End 01.04.2019 - 31.03.2023
Approved amount 704'666.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Pathophysiology
Immunology, Immunopathology

Keywords (5)

Inflammation; Colorectal carcinoma; Cancer immune therapy; Tumor Microenvironment; Protein Tyrosine Phosphatase N2

Lay Summary (German)

Lead
Alleine in der Schweiz leiden rund 30000 Menschen am kolorektalen Karzinom. Es ist die zweithäufigste Tumorerkrankung und die zweithäufigste, tumor-bedingte Todesursache weltweit. Insbesondere im fortgeschrittenen Stadium ist die Prognose für die betroffenen Patienten trotz neuartiger Therapien schlecht. Somit ist offensichtlich, dass die Identifizierung neuer Biomarker und Therapieansätze für Patienten mit kolorektalen Karzinom eine der grossen Herausforderungen der heutigen Medizin darstellt.
Lay summary

Inhalt und Ziel des Forschungsprojekts
Aufgrund unserer bisherigen Vorarbeiten sind wir überzeugt, dass die Protein Tyrosin Phosphatase Non-Receptor Type 2 (PTPN2) eine wichtige Rolle in der Entstehung des kolorektalen Karzinoms spielt. Allerdings ist die genaue Rolle von PTPN2 in der Entstehung des kolorektalen Karzinoms nur unzureichend verstanden. Unsere Hypothese ist, dass die Aktivierung von PTPN2 die Immunantwort des Körpers gegen die Tumorzellen abschwächt und auf diese Weise zum Tumorwachstum beiträgt. Die Expression von PTPN2 im Tumorgewebe könnte daher einen Biomarker für die Prognose von Patienten mit kolorektalem Karzinom darstellen. Eine Inaktivierung von PTPN2 könnte zudem ein neuer therapeutischer Ansatz für diese Patienten sein. Um unsere Hypothese zu verifizieren, wollen wir mit Hilfe von humanen Gewebeproben sowie Kolontumor-Mausmodellen die genaue molekulare Rolle von PTPN2 in der Entstehung des Kolonkarzinoms untersuchen und mögliche klinischen Anwendungsaspekte identifizieren.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts
Unsere Untersuchungen dienen dazu, die Rolle von PTPN2 in der Entstehung des kolorektalen Karzinoms näher zu definieren. Hierdurch sollen wichtige Erkenntnisse über die Regulationsmechanismen, welche zur Tumorentstehung führen, gewonnen werden. Die Ergebnisse sollen wichtige Erkenntnisse für die Identifizierung neuer Biomarker und therapeutischer Ansatzpunkte für die Behandlung des kolorektalen Karzinoms liefern und somit entscheidend zur Verbesserung der Behandlungsmöglichkeiten der betroffenen Patienten beitragen. Aufgrund der Vielzahl an betroffenen Menschen weltweit, ist die grosse Relevanz dieses Projektes offensichtlich. 

Direct link to Lay Summary Last update: 29.03.2019

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Associated projects

Number Title Start Funding scheme
166381 The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating inflammasome activation: implications for chronic intestinal inflammation 01.04.2016 Project funding (special)
177523 Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) 01.04.2018 Cohort Studies Large
170109 Dietary nanoparticles and their impact on Inflammatory Bowel Disease pathogenesis - Large Nested Project within the SWISS IBD Cohort Study 01.10.2016 Project funding (special)
166381 The role for Protein Tyrosine Phosphatase Non-receptor Type 2 in regulating inflammasome activation: implications for chronic intestinal inflammation 01.04.2016 Project funding (special)

Abstract

Colorectal carcinoma (CRC) is one of the most frequent cancers worldwide and a leading cause of cancer related deaths. The development of checkpoint inhibitor therapy, which promotes anti-cancer immune responses, has increased treatment efficacy for many malignant tumours, but only for a very small fraction of CRC patients, since the vast majority of CRC patients have tumours with low immunogenic potential. These patients would highly benefit from strategies that promote tumour immunogenicity. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates immune responses and deletion of PTPN2 in tumour cells seems to promote response to cancer immunotherapy in vitro. We have extensively demonstrated a role for PTPN2 in the pathogenesis of chronic intestinal inflammation and our most recent data suggest that loss of PTPN2 protects against the development of CRC in vivo. However, a role for PTPN2 in CRC pathogenesis has not yet been determined. Given its central anti-inflammatory role by modulating activation of the immune system, PTPN2 represents an interesting target for the development of new strategies aiming at increasing anti-tumour immune responses in humans.Taken together, the overall goal of our experiments is to evaluate whether PTPN2 function enhances development of CRC and to study whether PTPN2 might be a useful target to promote anti-tumour immune responses. Our hypotheses based on our previous data areAAs PTPN2 function is altered in human CRC tissue: Can it be used as prognostic biomarker? BLoss of functional PTPN2 diminishes the development of colon tumours in mouse models in vivo CPTPN2 deficiency in intestinal epithelial cells promotes cancer cell immunogenicity and cancer stem cell biology in vivo DLoss of PTPN2 in immune cells promotes CRC-associated anti-tumour immune responses in vivo To investigate our hypotheses, we will (A) analyse PTPN2 enzymatic activity, mRNA and protein levels in human CRC tissue and liver metastases using paraffin-embedded tissue slides and surgical specimen. We will study the potential of PTPN2 as a prognostic biomarker for therapy response and prognosis in CRC patients using a well-defined tissue microarray including 600 CRC tissue specimen. (B) We will demonstrate the relevance of PTPN2 for CRC development in vivo using PTPN2fl/flxVillinCre (intestinal epithelial cells), PTPN2fl/flxCD4Cre (CD4+ cells) and PTPN2fl/flxCD11cCre (dendritic cells) mouse models with a tissue-specific PTPN2 deletion and apply well-defined models of CRC, the inflammation-associated DSS/AOM model, the metastases-producing MC-38 orthotopic tumour cell injection model and a genetic model involving Cdx2Cre-APCfl/fl mice. (C) We will study the functional role for PTPN2 in cancer cell proliferation, apoptosis and cancer stem cell biology in vivo. Our mouse models will allow dissecting how PTPN2 contributes to CRC development by cell-type dependent, distinct molecular mechanisms using state-of-the-art molecular approaches, such as Cripsr/Cas9, intestinal organoids, CYTOF or RNAseq. (D) Using our CRC models, we will proof whether loss of functional PTPN2 in immune cells enhances the immunogenic potential of colon tumours and promotes anti-tumour immune responses what finally contributes to improved tumour control and immune-based anti-tumour therapy efficacy in vivo. Our experiments will determine the functional role for PTPN2 in the pathogenesis of CRC and define whether PTPN2 is involved in regulating anti-cancer immune responses in vivo. Our data will provide novel insights into the molecular mechanisms of CRC pathogenesis and might help to optimize therapeutic approaches in patients with non-immunogenic cancers, such as mainly CRC, what will finally result in improved patient care.
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