Metabolic impact on the histopathological growth patterns of liver metastasis from colorectal and breast cancer

• Applicant: Dr. Yiming Peng-Winkler
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521676159

Colorectal and breast cancers are among the most prevalent carcinomas and thus lead to a considerable burden of the healthcare system. Especially in their metastatic stage, treatment of these cancers is challenging. For both cancers, the liver is a major site for metastasis. Three histopathological growth patterns (HGPs) have been described for liver metastases of both cancers: The replacement type is characterized by replacement of the hepatocytes by the tumor cells without destroying the architecture of the liver. The desmoplastic type has a fibrous rim around the metastasis, which forms a distinct interface between the metastasis and healthy liver tissue. The pushing type shows a clear tumor-liver tissue interface without a collagenous wall and no cancer cells invade the liver parenchyma. One main feature to differentiate the growth patterns is their way of incorporating blood vessels. While the desmoplastic and the pushing types rely on angiogenesis of new capillaries, the replacement type uses pre-existing liver sinusoidal vessels (vessel co-option). However, little is known about the molecular mechanisms underlying these growth patterns. Recent studies suggest a crucial role of cellular metabolism on metastasis genesis and progression. Thus, the role of metabolism for the formation of the HGPs is a highly relevant area of investigation. The proposed project will apply spatial single cell metabolomics in combination with spatial transcriptomics and proteomics to liver metastasis samples from patients with colorectal or breast cancer to investigate the metabolic mechanisms underlying different HGPs. The data will be multiplexed to develop metabolic maps of the different HGPs and to characterize the role of metabolism for the formation of specific HGPs. Metabolism-related candidate transcripts differentially regulated in individual HGPs will be functionally investigated by knockdown and overexpression in mouse models. I further expect to elucidate the role of tumor origin on HGP-formation. The second part of the project will address the metabolic processes underlying vessel co-option, a characteristic feature of the replacement type HGP, which is associated with poor overall survival and poor response to anti-angiogenic therapy. I will use single cell in-situ multi-omic techniques to characterize the tumor microenvironment of the replacement HGP in comparison with the other two HGPs and the interaction with co-opted sinusoidal niche. Candidate transcripts will be characterized by knockdown or overexpression studies in mouse models to verify their role for replacement HGP formation and determine their potential for clinic therapy. The proposed project will grant a comprehensive analysis of the metabolic processes underlying breast and colorectal cancer liver metastases, provide a basis for further research in the role of metabolism for different metastasis types and identify potential therapeutic targets.

• DFG Programme: WBP Fellowship
• International Connection: Belgium
• Host: Professorin Dr. Sarah-Maria Fendt