PhD Scientific Days 2020

Molecular Sciences I. Lectures

Intratumoral Cellular Heterogeneity Critically Influences the Uptake of Extracellular Vesicles, a Potential Tool for Targeted Therapies

Előadó neve

Andrea, Kelemen, MSc

Előadó munkahelye

Department of Genetics, Cell- and Immunbiology

Előadó telefonszáma

+36304670714

Előadó e-mail címe

kelemen.andrea93@gmail.com

Az előadás címe

Intratumoral Cellular Heterogeneity Critically Influences the Uptake of Extracellular Vesicles, a Potential Tool for Targeted Therapies

Szerző(k) neve és munkahelye

Semmelweis University, Department of Genetics, Cell and Immunobiology, Molecular Cancer Research Group

Szekció

Molecular Sciences I. Lectures

Language of the presentation

English

Section, first choice

Molecular Sciences

Section, second choice

Pathology and Oncology

Összefoglaló szövege

Colorectal cancer (CRC) is one of the most abundant cancer types in the developed countries. With the exception of some cases, the role of intratumoral heterogeneity of cancer cells is not yet well known. Patient-derived 3D organoids represent one of the most modern methods to study this heterogeneity. Extracellular vesicles (EVs) are membrane-surrounded structures participating in the intercellular communication and they hold a great promise for targeted therapies. IFITM1 plays a critical role in membrane-enclosed virus uptake, raising the possibility that this molecule regulates the effects of EVs as well. Furthermore, there is a strong negative correlation between the amount of cancer-associated fibroblasts (CAF) and the time to disease relapse in CRC. Thus, we aimed at i) determining the heterogeneity in the expression level of IFITM1 and ii) its role in fibroblast EV uptake in CRC.
The Medical Research Council of Hungary approved our experiments and informed consent was obtained from patients. We prepared single cells from organoids and sorted different cell subpopulations. We analyzed proliferating cells, organoid diameter, protein and RNA level in patient-derived normal colon, adenoma and CRC organoids. We detected EVs by antibody-coated beads and by Nanoparticle Tracking Analysis (NTA). The uptake of labelled large EVs was visualized by confocal microscopy and the functional importance of the uptake was detected by immunocytochemistry.
We observed a higher expression of IFITM1 in adenomas and CRCs than in the normal colon. IFITM1high CRC cell-derived organoids were larger and they contained more Ki67+ proliferating cells compared to IFITM1low organoids, however, we found no difference in the percentage of apoptotic cells. Whereas the two cell populations did not differ in their EV release, IFITM1low CRC cells took up more EVs. Furthermore, adding fibroblast-derived EVs to IFITM1low organoids resulted in a more pronounced increase in Ki67+ cell number compared to IFITM1high cells, leading to the disappearance of the difference in organoid size.
Our results indicate that the intra-tumoral heterogeneity results in tumor cell subpopulations with different EV uptake ability, leading to different proliferation potential. Thus, this intra-tumoral heterogeneity may be a critical factor when designing EV-based targeted therapy in CRC.

Additional Information

Supervisor: Zoltán Wiener
E-mail address: zoltan.wiener@gmail.com

This work was funded by OTKA-NN 118018 (National Research, Development and Innovation Office, Hungary), by the National Excellence Program in Higher Education (Ministry of Human Resources, Hungary) and by the Richter Gedeon Excellence PhD Scholarship of Richter Gedeon Talentum Foundation.

Bemutatás módja

Szóbeli

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

4652

Start

10:50

End

11:05

Authors (legacy)

Semmelweis University, Department of Genetics, Cell and Immunobiology, Molecular Cancer Research Group