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Transient receptor potential melastatin-4 channel (TRPM4) in colorectal cancer

English title Transient receptor potential melastatin-4 channel (TRPM4) in colorectal cancer
Applicant Peinelt Christine
Number 173155
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Physiology : other topics
Start/End 01.09.2017 - 31.03.2022
Approved amount 581'770.00
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All Disciplines (2)

Discipline
Physiology : other topics
Experimental Cancer Research

Keywords (5)

SOCE; Colorectal Cancer; Ion channel; TRPM4; Calcium

Lay Summary (German)

Lead
Ionenkanäle sind porenformende Proteine in biologischen Membranen. Durch sie können geladene Teilchen (Ionen) in und aus der Zelle gelangen. Ionen spielen in der Steuerung vieler Zellfunktionen eine Rolle. In vielen Krankheitsbildern in denen Zellfunktionen gestört sind, liegt daher auch die Dysregulation von Ionenkanälen vor.
Lay summary

Calciumionen sind ein Schlüsselsignal zur Steuerung von Zellfunktionen zum Beispiel dem programmierten Zelltod (Apoptose), Zellbewegungen (Migration) und Zellvermehrung (Proliferation). Calciumkanäle wie zum Beispiel speicheraktivierte Calciumkanäle (SOCE, STIM/Orai) sind in unterschiedlichen Krebsarten dysreguliert, und tragen zu den sogenannten Cancer Hallmarks (Kennzeichen für Krebs: ungehemmte Proliferation, Unfähigkeit zur Apoptose und erhöhte Zellmigration) bei.
Die Proteinfamilie der TRP (transient receptor potential) Kanäle bildet eine vielseitige Ionenkanalfamilie, welche unter anderem in die Schmerz- und Geschmackserkennung involviert ist. Das TRP Familienmitglied TRPM4 leitet Natriumionen und kann dadurch die Calciumhomöostase der Zellen regulieren. Dysregulationen von TRPM4 kann mit Herzpathophysiologie und der Migrationsfähigkeit von Immun- und Prostatakrebszellen assoziiert sein.
In unserem Forschungsprojekt untersuchen wir die Rolle von TRPM4 in Darmkrebs. Wir untersuchen eine mögliche Dysregulation von TRPM4 und Kalziumsignalen in Darmkrebszellen, eine Beteiligung an den Cancer Hallmark Funktionen und die zugrundeliegenden Mechanismen.

Direct link to Lay Summary Last update: 09.05.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
TRP Channels in Digestive Tract Cancers
Stokłosa Paulina, Borgström Anna, Kappel Sven, Peinelt Christine (2020), TRP Channels in Digestive Tract Cancers, in International Journal of Molecular Sciences, 21(5), 1877-1877.
TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells
Kappel Sven, Stokłosa Paulina, Hauert Barbara, Ross‐Kaschitza Daniela, Borgström Anna, Baur Roland, Galván José A., Zlobec Inti, Peinelt Christine (2019), TRPM4 is highly expressed in human colorectal tumor buds and contributes to proliferation, cell cycle, and invasion of colorectal cancer cells, in Molecular Oncology, 13(11), 2393-2405.

Collaboration

Group / person Country
Types of collaboration
Inti Zlobec, Institute of Pathology, TRU, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
98th Meeting of the German Physiological Society Talk given at a conference The role of TRPM4 ion channel in colorectal and prostate cancer 30.09.2019 Ulm, Germany Stoklosa Paulina;
Swiss Physiology Meeting Talk given at a conference The role of TRPM4 mediated currents in colorectal cancer cells viability and cell cycle 03.09.2019 Bern, Switzerland Stoklosa Paulina;
BioMedical Transporters Conference Poster The role of TRPM4 ion channel in colorectal cancer 04.08.2019 Lucerne, Switzerland Kappel Sven; Hauert Barbara; Peinelt Christine; Stoklosa Paulina;
63rd Biophysical Society Meeting Poster Role of TRPM4 channel in colorectal and prostate cancer 02.03.2019 Baltimore, United States of America Hauert Barbara; Kappel Sven; Peinelt Christine; Stoklosa Paulina;
LS2 Annual Meeting 2019 Talk given at a conference Possible role of TRPM4 in calcium-mediated exocytosis in colorectal cancer cell line HCT116 14.02.2019 Schweiz, Switzerland Stoklosa Paulina;
LS2 Annual Meeting 2019 Talk given at a conference TRPM4 controls cancer hallmark functions in colorectal cancer 14.02.2019 Zürich, Switzerland Kappel Sven;
Swiss Physiology Meeting Poster Potential role of Transient receptor potential melastatin channel 4 (TRPM4) in calcium-mediated exocytosis in colorectal cancer cell line HCT116 04.09.2018 Fribourg, Switzerland Stoklosa Paulina; Peinelt Christine; Hauert Barbara; Kappel Sven;
2018FASEB Science Research Conference on Calcium and Cell Function Talk given at a conference Calcium in Oncogenesis 10.06.2018 Lake Tahoe, United States of America Kappel Sven; Peinelt Christine;
62nd Biophysical Society Meeting Poster Investigation of TRPM4 channel in cancer cell systems 17.02.2018 San Francisco, United States of America Peinelt Christine; Kappel Sven; Stoklosa Paulina;


Self-organised

Title Date Place
Swiss Physiology Meeting 03.09.2019 Bern, Switzerland

Awards

Title Year
Posterprize 2019

Abstract

Colorectal cancer (CRC) is the third most common cancer and worldwide, roughly 1.36 million patients are diagnosed with CRC each year. As in other types of cancer, in CRC imbalances in store-operated Ca2+ entry (SOCE) contribute to several cancer hallmarks, functions such as increased proliferation, a reduced ability to induce cell death, and invasion. Our preliminary data demonstrate that in CRC cells intracellular Ca2+ activates transient receptor potential melastatin-4 channel (TRPM4) and that TRPM4 conducts large Na+ currents. TRPM4-mediated Na+ influx can depolarize the membrane potential, thereby decreasing the driving force for Ca2+ and thus reducing SOCE signals as a feedback mechanism. Our preliminary data show that TRPM4 is a negative regulator for SOCE in CRC cells. In CRC cells, TRPM4 expression levels seem to be impaired. Within this project, we aim to study the physiological and pathophysiological role of TRPM4 in CRC cells. We will test for TRPM4 expression levels in human CRC tissue slices. We plan to use cellular assays (proliferation, apoptosis and migration) to investigate the role of TRPM4 in CRC cells. With this we plan to test for TRPM4 as putative therapeutic target in CRC. In addition, we plan to determine the potential of different TRPM4 blockers that are currently being developed to alter cancer hallmark functions. In order to investigate the mechanism(s) that underlie(s) TRPM4’s role in cellular functions (modulation of SOCE, Na+ influx or protein-protein interaction), we plan different sets of experiments including Ca2+ and Na+ imaging assays and analysis of different TRPM4 constructs that either conduct Na+ (TRPM4WT) or Ca2+ (TRPM4Ca2+) and a dominant negative mutant (TRPM4D984A). Taken together, within our proposal we plan to investigate the role of TRPM4 in CRC and the regulation of TRPM4 as a versatile mechanism in cancer cells.
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