PhD Scientific Days 2022

Molecular Sciences III. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Patient-derived colorectal cancer organoids to study a potential combination therapy

Előadó neve

Soós, András Áron

Előadó munkahelye

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

Előadó telefonszáma

06-20/670-1679

Előadó e-mail címe

soos.andras@phd.semmelweis.hu

Az előadás címe

Patient-derived colorectal cancer organoids to study a potential combination therapy

Szerző(k) neve és munkahelye

András Áron Soós1, Andrea Kelemen1, Zoltán Wiener1
1 Semmelweis University Department of Genetics, Cell and Immunobiology, Molecular Cancer Biology Research Group, Budapest

Bemutatás módja

Szóbeli

Szekció

Molecular Sciences III. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Language of the presentation

English

Preferred session

Molecular Sciences

Összefoglaló szövege

Colorectal cancer (CRC) is one of the most prevalent cancer types. CRC shows an intratumoral cellular heterogeneity: the CD44 positive tumor cells have a higher tumor-initiating capacity. Three-dimensional patient-derived organoids maintain the cellular heterogeneity of the original tissues, thus, they are one of the best in vitro models of human cancers. Accumulation of collagen I in the extracellular matrix (ECM) is a critical process for the invasion of CRC cells. Although different chemotherapy-based medications exist, new targeted therapies are required. A recent study found a synergistic effect between the MEK1/2 inhibitor Trametinib and the heat shock protein-90 inhibitor PU-H71 in pancreatic adenocarcinoma model systems.
Thus, we studied the effectiveness of Trametinib and PU-H71 in CRC. Moreover, we examined whether collagen I in the ECM and cellular heterogeneity modify the chemosensitivity of CRC organoids.
We cultured CRC patient-derived organoids in laminin-rich Matrigel or collagen I as 3D matrix. Cell viability was measured with the Cell-TiterGlo 3D assay and CD44low and CD44high cells were isolated with fluorescent cell sorting.
When calculating the IC50 values in Matrigel and collagen I cultures, we found no change for Trametinib, but the IC50 value of PU-H71 increased in collagen cultures. When using these agents as a combination therapy, we observed a synergistic effect both in Matrigel and in collagen I. In addition, we found an increased CD44 expression level in collagen I by flow cytometry. To study the molecular background of the change in the chemosensitivity in collagen I, we established organoids from sorted CD44low and CD44high cells. Although CD44low and CD44high organoids did not show a differential sensitivity to Trametinib, CD44high organoids showed a higher resistance to PU-H71. Moreover, Trametinib and PU-H71 had a higher effect on CD44low CRC organoids compared to CD44high organoids as a combination therapy.
Collectively, we proved that Trametinib and PU-H71 are potential combination targeted therapy in CRC. In addition, we identified the accumulation of collagen in the ECM as a factor that promotes stemness and chemoresistance.
Funding: EFOP-3.6.3-VEKOP-16-2017-00009 (AÁS); NTP-NFTÖ-21-B-0149 (AÁS), János Bolyai Research Fellowship (ZW, BO/00131/20/8), OTKA 137554 and TKP2021-EGA-24 (ZW).

University and Doctoral School

Semmelweis University, Doctoral School of Molecular Medicine

Supervisor

Dr. Zoltán Wiener

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

5978

Start

11:30

End

11:45

Authors (legacy)

András Áron Soós1, Andrea Kelemen1, Zoltán Wiener1
1 Semmelweis University Department of Genetics, Cell and Immunobiology, Molecular Cancer Biology Research Group, Budapest