TGFβ signalling pathway impacts brain metastases profiles in locally advanced colorectal cancer

Sven Jacob; Ilja Balonov; Vindi Jurinovic; Christian Heiliger; Tengis Tschaidse; Jörg Kumbrink; Thomas Kirchner; Jens Werner; Martin K Angele; Marlies Michl; Jens Neumann

doi:10.1007/s10585-024-10277-3

TGFβ signalling pathway impacts brain metastases profiles in locally advanced colorectal cancer

Clin Exp Metastasis. 2024 Mar 18. doi: 10.1007/s10585-024-10277-3. Online ahead of print.

Authors

Affiliations

¹ Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany.
² The Institute for Medical Information Processing, Ludwig-Maximilians-University (LMU) Munich, Biometry, and Epidemiology, Munich, Germany.
³ Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany.
⁴ Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.
⁵ Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University (LMU) Munich, Marchioninistr. 15, 81377, Munich, Germany. jens.neumann@med.uni-muenchen.de.

^# Contributed equally.

PMID: 38498101
DOI: 10.1007/s10585-024-10277-3

Abstract

Rationale: Colorectal Cancer (CRC) represents the third most common type of cancer in Germany and the second most common cancer-related cause of death worldwide. Distant metastases are still the main limit for patient survival. While liver metastases as well as peritoneal carcinomatosis can often either be resected or treated with systemic therapy, little options remain for brain metastases. Additionally, a number of studies has already investigated hepatic, peritoneal, pulmonary as well as continuing distant metastases in colorectal cancer. Yet, with respect to tumor biology and brain metastases, little is known so far.

Material and methods: Two cohorts, M0 without distant spread and BRA with brain metastases were build. RNA was isolated from paraffin embedded specimen. Gene expression was performed by an RNA NanoString-Analysis using the nCounter® PanCancer Progression Panel by NanoString-Technologies (Hamburg, Germany). Results were analysed by principal component analysis, gene expression and pathway analysis using commonly available databases such as KEGG as benchmark for comparison.

Results: We were able to determine a gene signature that provides a sophisticated group separation between M0 and BRA using principal component analysis. All genes with strong loading characteristics on principal component 1 were cross-referenced with the subsequently performed accurate gene set enrichment analysis (GSEA). The GSEA revealed a clear dysregulation of the TGFβ pathway in compared cohorts M0 and BRA. Interestingly, the targeted pathways analysis of the identified genes confirmed that in fact almost all strong loading genes of PC1 play a role in the TGFβ pathway.

Conclusion: Our results suggest the TGFβ pathway as a crucial player in the development of brain metastases in primary CRC. In some types of colorectal cancer, downregulation of the TGFβ pathway might hinder primary colorectal cancer to metastasize to the nervous system. While the paradoxical functioning of the TGFβ pathway is still not fully understood, these shed light on yet another clinical implication of this complex pathway.

Keywords: Brain metastasis; Colorectal cancer; Gene signature; Hematogenous spread; Pathway analysis; TGFβ signalling pathway influences CRC brain metastasis.