The role of tumor endothelial marker 1 in lung metastasis

master's thesis

• Title (croatian): Uloga tumorskog endotelnog markera 1 u metastaziranju pluća
• Author: Dorian Dragičević
• Mentor: Stefan Offermanns (mentor)
• Mentor: Petra Korać (komentor)
• Committee member: Petra Korać (predsjednik povjerenstva)
• Committee member: Inga Urlić (član povjerenstva)
• Committee member: Biljana Balen (član povjerenstva)
• Committee member: Petra Peharec Štefanić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2022-09-27, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Cancer relapse is driven by dormant tumor cells that are able to reactivate after perturbations in
the microenvironmental niche. Endothelium-derived protein multimerin 2 (MMRN2) is
hypothesized to induce tumor reawakening through the interaction with tumor endothelial
marker 1 (TEM1). The main objective of this study was to assess the MMRN2-TEM1 axis in
reactivation and proliferation of B16F10 melanoma and E0771 breast cancer cells, and
elucidate function of TEM1 in lung metastasis. The MMRN2-TEM1 axis, induced by a coculture system comprised of endothelial cells and tumor cells, has demonstrated to stimulate
phosphorylation of ERK1/2. Individual addition of PDGFB and MMRN2 fragments to dormant
tumor cells caused their reactivation, conceivably through the TEM1-PDGFRB pathway. In
vivo results have shown that absence of TEM1 does not influence primary tumor growth nor
extravasation, but reduces macrometastasis formation in both intravenous and resection models
of lung metastasis. These in vivo results suggest that TEM1 could be implicated in tumor mass
dormancy. Computational models have shown significant correlation of TEM1 and PDGFRB
as a prediction marker of low survival rates and higher relapse in various tumor types.
Therefore, this study presents a pioneering research in defining the MMRN2-TEM1
reactivation axis as a potential target for state-of-the-art, personalized therapies intended for
patients in remission.

Abstract (croatian)

Ponovnu pojavu tumora uzrokuju dormantne tumorske stanice koje su sposobne reaktivirati se
uslijed promjena u mikrookolišnoj niši. Za endotelni protein multimerin 2 (MMRN2) se
pretpostavlja da inducira nastanak tumora, stupanjem u interakciju s tumorskim endotelnim
markerom 1 (TEM1). Glavni cilj ovoga rada bio je procijeniti ulogu osi MMRN2-TEM1 u
reaktivaciji i proliferaciji stanica melanoma B16F10 i stanica tumora dojke E0771 te razjasniti
funkciju proteina TEM1 u metastaziranju pluća. Pokazano je da os MMRN2-TEM1, inducirana
kokulturom endotelnih stanica i tumorskih stanica, može stimulirati fosforilaciju proteina
ERK1/2. Pojedinačni dodaci proteina PDGFRB i fragmenata MMRN2 dormantnim tumorskim
stanicama uzrokovali su njihovu reaktivaciju, potencijalno signalnim putem TEM1-PDGFRB.
Rezultati in vivo su pokazali da nedostatak proteina TEM1 ne utječe na rast primarnog tumora
ni proces ekstravazacije, ali smanjuje formaciju makrometastaza u intravenoznom i
resekcijskom modelu plućnog metastaziranja. Navedeni rezultati in vivo upućuju na to da
protein TEM1 može biti uključen u regulaciju tumorske mase tijekom dormancije. Računalni
modeli su ukazali na značajnu povezanost proteina TEM1 i proteina PDGFRB kao
predikcijskog markera smanjenog preživljenja i češće ponovne pojave tumora kod brojnih
tipova tumora. Ovaj rad predstavlja inicijalno istraživanje u definiranju reaktivacijske osi
MMRN2-TEM1, kao potencijalne mete suvremenih, personaliziranih terapija namijenjenih
pacijentima u remisiji.

• Keywords: tumor dormancy; tumor reactivation; perivascular niche; multimerin 2; melanoma; breast cancer
• Keywords (croatian): dormancija tumora; reaktivacija tumora; perivaskularna niša; multimerin 2; melanom; tumor dojke
• Language: english
• URN:NBN: urn:nbn:hr:217:968120
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2024-09-27
• Created on: 2022-10-21 10:13:53