Institute of Pathology, Experimental and Molecular Pathology

Project description:

Colorectal cancer (CRC) arises through stepwise genetic and microenvironmental changes. The most frequent early event is APC loss-of-function (80–85% of sporadic cases), which activates Wnt/β-catenin signaling and induces c-Myc–driven proliferation, leading to aberrant crypt foci and adenomas. APC-mutant cells recruit macrophages with an M2 phenotype and directly activate cancer associated fibroblasts/CAFs, initiating extracellular matrix remodeling. With progression, KRAS mutations (30–50% of adenomas) drive MAPK/ERK-mediated proliferation, promote M2 macrophages via IL-6/IL-8 and Arg1, and sustain tumor survival through a CAF–TAM feedback loop under hypoxia. In later stages, TP53 mutations drive malignant transformation by inducing genomic instability, reprogramming macrophages via exosomal miR-1246, shifting CAFs toward MMP2/9-producing phenotypes, and enhancing immune evasion through PD-L1.

Our lab is focusing on the c-MYC effector AP4 (TFAP4) (for review see Matthew et al. 2021) and the p53 effectors miR-34a and 14-3-3σ. They function as key regulators linking genetic context to alterations in cancer-relevant cellular processes (for review see Matthew et al. 2021, Hermeking, 2012, 2003). For example, the microRNA miR-34a has been shown to regulate cell proliferation, senescence, autophagy, apoptosis and stemness. More recently, we found that miR-34a also acts tumor suppressive in tumor-associated macrophages (König et al. 2024).

In the proposed project we aim to further characterize the combined effects of c-MYC activation and p53 inactivation on the micro-environment of colorectal cancers. For this we will use genetic mouse models of CRC and tumoroids derived from these. Key findings will be validated on human tumors and further analyzed in human CRC cell lines.

_{References:
MicroRNAs in the p53 network: micromanagement of tumour suppression.
Hermeking, H (2012). Nature Reviews Cancer 12, 613-626
The 14-3-3 cancer connection. Hermeking, H. (2003), Nature Reviews Cancer 3, 931-943, doi: 10.1038/nrc1230.PMID: 14737123
Transcription Factor AP4 Mediates Decisions at the Crossroad of Cell Fate: To Divide, Age, or Die
Matthew M. W., Sancy M.J., Hermeking, H. and Kay, S. (2021)
Cancers 13 (4), 676, doi: 10.3390/cancers13040676, PMID: 33567514
Myeloid MiR34a suppresses colitis-associated colon cancer: characterization of mediators by single-cell RNA sequencing.
König J, Rokavec M, Öner-Ziegler MG, Fei Y and Hermeking H (2025)
Cell Death & Differentiation 32(2):225-241, doi: 10.1038/s41418-024-01380-9, PMID: 39425000}