Metastasis predisposing extracellular matrix architecture in colorectal cancer (PredisposAL)

• Applicants: Professorin Dr.-Ing. Priscilla Briquez, Ph.D.; Professor Dr. Stefan Fichtner-Feigl; Dr. Raphael Reuten
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539446614

The extracellular matrix (ECM) is the non-cellular mass outside cells, that is built, regenerated, and remodeled by various cell types. Although the ECM impacts all hallmarks of cancer, the functional role of the baseline host ECM architecture on metastasis formation has not been studied. Cancer cells must travel through the ECM on their route to colonize secondary sites establishing metastasis. Most colorectal cancer (CRC)-related deaths approximately 80% are caused by metastasis. However, the metastatic process of CRC remains elusive highlighting the utmost need of smart concepts to identify novel diagnostic and therapeutic tools. Based on the necessity to diagnose metastasis as early as possible to guide the therapeutic regimen, we propose the concept of a metastasis predisposing ECM architecture in CRC. Here, we envision that the organ-specific baseline host ECM architecture controls CRC cell invasion to the liver, lung, and peritoneum. This novel concept is strongly supported by our recent findings highlighting that stiffness levels of the baseline basement membrane (basM), a specialized type of the ECM, determine metastasis formation in several cancers independent of cancer-mediated alterations. Mechanistically, the core matrisome protein netrin-4 binds with high-affinity to laminin, thereby increasing matrix pore size and simultaneously decreasing basM stiffness, which counterintuitively restricts cancer cell-basM crossing. Remarkably, our data demonstrate that the molecular ratio of netrin-4 and laminin determines basM stiffness, hence, the higher the netrin-4/laminin ratio the softer the basM and the less metastasis thereby extending patient survival. Fig. 1 | Project overview. In our study we aim to decipher the impact of basM stiffness on CRC metastasis (aim 1), its diagnostic power (aim 2), and its potential as a therapeutic target (aim 3). In our alternative approach, we plan to decode the regulatory network of the basM softening molecule netrin-4 to identify new diagnostic markers and targets for the next funding period (dotted lines). Expected outcomes are boxed in blue. Mathematical modelling, bioinformatic and biophysical analyses, and functional in vitro and in vivo invasion studies not only suggest that basM stiffness generally instructs the metastatic activity of cancer cells independent of type and mutation status but also paves the way for a potential therapeutic approach to normalize netrin-4 levels in patients predisposed to develop future metastasis. To address our hypothesis, we aim to (i) determine the functional role of basM stiffness on CRC-related metastasis formation and progression, (ii) decipher the impact of basM stiffness levels on human CRC progression, and (iii) investigate potential therapy regimens using chimeric drugs with basM softening and anti-angiogenic activities.

• DFG Programme: Research Grants