RNAseq data obtained from the Greten Lab at the Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt/Main, Germany
Now published under DOI: 10.1016/j.ccell.2022.01.004; data is available under NCBI-GEO: GSE190006
- model organism: mouse
- APTK tumor organoids: mutant for Apc, Trp53, Tgfbr2 and K-ras
- APTKA tumor organoids: additionally express myristoylated AKT (leads to constitutive Act/Pkb activation)
- fibroblasts were treated with APTK or APTKA organoid supernatant for 24h
- a separate analysis will analyse the same CAFs using stable-isotope-labelling to look at pathway activities
Cancer-associated fibroblasts (CAFs) are one of the most prominent and plastic cell types in the tumor microenvironment (TME) that play key roles during tumorigenesis (Schmitt & Greten, 2021). Not only do CAFs comprise a heterogeneous population of activated cells that are derived from a variety of sources such as fibroblasts, adipocytes, stellate cells, and other cell types, but in addition distinct CAF subtypes can mediate different tumorigenic responses. For instance, depending on their proximity to cancer cells and their response to IL-1R or TGF-b activation, CAFs have been shown to differentiate into functionally distinct populations of either inflammatory CAFs (iCAFs) or myofibroblasts (myCAFs) (Öhlund et al., 2017).
In colorectal cancer (CRC), the third most common type of cancer worldwide (Ferlay et al., 2019), CAFs are the hallmark of the mesenchymal phenotype CMS4, which correlates with the poorest survival rate among the four consensus molecular subtypes (CMS) (Guinney et al., 2015). Recently, Varga et al. (2020) generated the first mouse model resembling the human CMS4 subtype, showing that orthothopic transplantation of tumor organoids mutant for Apc, Trp53, Tgfbr2 and K-ras (APTK) induced single invasive tumors that metastasized to the liver in 10% of the cases. In contrast, transplantation of APTK organoids that expressed an additionally myristoylated AKT (APTKA), lead to a stronger stromal response along with a more aggressive tumor phenotype that metastasized to the liver in 60% of the cases. These results suggest that cancer cells with differing mutations can induce distinct CAF subtypes that influence disease severity.
The aim of the current project is to characterize the different CAF subtypes induced by APTK and APTKA mouse tumor organoid supernatant. Fibroblasts were treated with organoid supernatant for 24h before sequencing. The analysis focuses on cell metabolism to provide a comprehensive picture of metabolic reprogramming of different CAF subtypes.
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Öhlund, D., Handly-Santana, A., Biffi, G. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. Journal of Experimental Medicine 214: 579–596 (2017).
Schmitt, M. & Greten, F. R. The inflammatory pathogenesis of colorectal cancer. Nature Reviews Immunology pp. 1–15 (2021).
Varga, J., Nicolas, A., Petrocelli, V. et al. AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer. Journal of Experimental Medicine 217 (2020).