PhD Scientific Days 2025

Molecular Medicine I.

The Aggressive Colorectal Cancer Subtype Marker HTR2B has a Dual Role Depending on the Tumor Microenvironment

Name of the presenter

Carmi Idan

Institute/workplace of the presenter

Department of Genetics, Cell- and Immunobiology

Authors

Idan Carmi¹, Adrián Orosz¹, Szabolcs Hajdó¹, Anikó Zeöld¹, Tamás Tölgyes², Kristóf Dede², Attila Bursics², Dr. Zoltán Wiener¹

1: Department of Genetics, Cell- and Immunobiology
2: Uzsoki Teaching Hospital

Text of the abstract

Colorectal cancer (CRC) is amongst the most frequent cancer types. The HTR2B tumor marker, which is expressed heterogenously intra- and inter-tumorally, is used prognostically to identify an aggressive subtype of CRC with epithelial-mesenchymal transition (EMT), the accumulation of fibroblasts, and a dismal prognosis. Similarly, NOTCH3 activation promotes cancer development in a model of the aggressive mesenchymal CRC. For CRC, the accumulation of collagen-I in the extracellular matrix (ECM) correlates with an adverse prognosis.

To uncover the role of HTR2B activity in CRC tumorigenesis.

Patient-derived organoids (PDOs), which maintain the intratumoral heterogeneity and represent a modern tool to study human cancers, were isolated and cultured under different conditions. Cells were sorted into high and low-expressing populations for HTR2B or NOTCH3 for specific experiments. Cell viability was determined with a luminescence assay, while survival and proliferative potential were determined with flow cytometry (FC). Confocal and light microscopic image analysis were used to quantify changes in invasive potential and EMT.

Serotonin or an HTR2B agonist reduced cellular survival only in carbohydrate-deprived medium. In contrast, collagen-I ECM led to serotonin-induced invasion, especially in organoids derived from HTR2B+ tumor cells. CRC cells positive for HTR2B highly expressed NOTCH3 and NOTCH target genes. Similar to HTR2B+ organoids, NOTCH3+ cells had increased levels of EMT markers. HTR2B+ cells also showed a higher invasion potential in collagen compared to HTR2B negative cells. Hence, analogous to HTR2B stimulation, inhibition of Notch activity changed EMT marker levels.

Collectively, the serotonin receptor HTR2B+ marks a CRC cell population with increased proliferative and invasive potential only in specific ECM, and serotonin has a dual role, under unfavorable conditions, and in ECM enriched for collagen. Furthermore, the cell population with active NOTCH signaling shares features with HTR2B+ cells and similarly promotes aggressive tumoral behavior.

Funding: K137554, 2024-1.2.3-HU-RIZONT-2024-00003 (National Research, Development and Innovation Office, Hungary), TKP2021-EGA-24 (Ministry of Innovation and Technology of Hungary). IC is supported by Semmelweis 250+ funding. Ethical permission: TUKEB 2015, 51323-4/2015/EKU.