PhD Scientific Days 2023

Molecular Sciences I.

The importance of fibroblast heterogeneity in the tumorigenesis of colorectal cancer

Előadó neve

Soós, András Áron

Neptun code

QJ1DOE

Előadó munkahelye

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

Előadó telefonszáma

+36206701679

Előadó e-mail címe

soos.andras@phd.semmelweis.hu

Az előadás címe

The importance of fibroblast heterogeneity in the tumorigenesis of colorectal cancer

Szerző(k) neve és munkahelye

András Áron Soós1, Adrián Orosz1, Zoltán Wiener1
1Semmelweis University Department of Genetics, Cell and Immunobiology, Molecular Cancer Biology Research Group, Budapest

Bemutatás módja

Szóbeli

Szekció

Molecular Sciences I.

Language of the presentation

English

Preferred session

Molecular Sciences

Összefoglaló szövege

The accumulation of cancer-associated fibroblasts (CAF) in the stroma, results in a worse patient survival in colorectal cancer (CRC). However, classification of the CAFs is still not resolved in CRC. A recent study proved that the CD142low fibroblast population of the colon was associated with inflammatory bowel disease. Interestingly, two CAF subtypes have been identified in pancreatic ductal adenocarcinoma. Whereas the myofibroblastic myCAFs produce primarily extracellular matrix components, the other CAFs (iCAFs) secrete inflammatory cytokines. Moreover, CAFs provide a niche for CRC cells by secreting growth factors. Characterizing stromal fibroblasts and therapeutic targeting of both cancer and stromal cells in CRC are thus major challenges.
We aimed at characterizing fibroblast populations that support CRC tumorigenesis. We then tested novel compounds on CRC cells and fibroblasts, and we compared their effects on the tumor supporting fibroblast subpopulation. To accomplish our aims, we applied patient-derived organoids that maintain the cellular heterogeneity of the original tissue.
Interestingly, we found that fluorescently sorted CD142high fibroblasts are in a mixed myCAF-iCAF state. Furthermore, CD142high fibroblasts increased the organoid forming efficiency and the percentage of KI67+ proliferating cells of organoids compared to CD142low fibroblasts in cocultures. When testing novel compounds, we observed that CRC fibroblasts showed a higher resistance for MEKi (MEK inhibitor) and the combined MEKi+Hsp90i (heat shock protein-90 inhibitor), but they were more sensitive to Bcli (Bcl-xL inhibitor), JQ1 (bromodomain epigenetic inhibitor) and the combination of these two drugs compared to CRC organoids. Importantly, all the combinations of these drugs acted synergistically on CRC organoids. Interestingly, when applying the IC50 concentrations of the compounds, we observed a decreased percentage of CD142+ fibroblasts for Hsp90i, but not for JQ1 or Bcli.
Collectively, these data suggest that fibroblasts with differential CD142 levels have different organoid initializing effects in CRC. Since fibroblasts are sensitive to Bcli and Hsp90i results in a negative selection of the tumor promoting CD142high fibroblasts, this combination may target both tumor cells and stomal fibroblasts efficiently in CRC.
Funding: OTKA137554, TKP2021-EGA-24, SE250+ fellowship

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

09:30

End

09:45

Authors (legacy)

András Áron Soós1, Adrián Orosz1, Zoltán Wiener1
1Semmelweis University Department of Genetics, Cell and Immunobiology, Molecular Cancer Biology Research Group, Budapest