29P - The effect of cancer associated fibroblast-derived activin A on colorectal cancer progression

Background

Colorectal cancer (CRC) is one of the most common cancers worldwide. In particular, the yearly mortality emphasizes the limited spectrum of treatment possibilities. The tumor microenvironment with its relevant influence on malignant tumor initiation, progression and chemoresistance represents a promising target for cancer therapeutics. Especially cancer-associated fibroblasts (CAFs) are of importance in carcinogenesis as they are involved in tumorigenesis, metastasis, inflammatory responses, and extracellular matrix changes. Based on preliminary data, we found upregulated expression of INHBA, a gene encoding for the βA subunit of the TGFβ superfamily members Activin A, Activin AB and Inhibin A, in the stromal compartment of human CRC. Therefore, we wanted to investigate the autocrine and paracrine functional consequences of CAF-secreted Activin A in CRC.

Methods

We knocked down INHBA in primary patient-derived CAFs and used in vitro 3D collagen gel assays, flow cytometry, immunofluorescence, secretome analysis and Western blotting to check the autocrine effects of Activin A on CAFs. Regarding the paracrine impact on tumor cells and immune cells, we employed 3D co- and triple-culture collagen gel assays to determine the impact of CAF-derived Activin A. Here, we focused on proliferation, apoptosis and invasion levels of tumor cells as well as on monocyte differentiation, myeloid cell plasticity and T-cell activation.

Results

Our data demonstrate that CAFs expressing INHBA show a pro-proliferative, pro-motile and pro-contractile phenotype. Furthermore, the secretome and plasticity of CAFs were notably modified by the INHBA knockdown. Additionally, CAF-derived Activin A seems to influence various aspects of tumor progression and the plasticity of immune cells.

Conclusions

Together, our results indicate key functions of CAF-derived Activin A in CRC progression suggesting a potential novel therapeutic target.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Austrian Academy of Sciences.

Disclosure

All authors have declared no conflicts of interest.