Wspólnotowy Serwis Informacyjny Badan i Rozwoju - CORDIS

Final Report Summary - CAFFORCE (Physical forces driving fibroblast-led cancer cell migration)

Cancer progression is increasingly attributed to the aberrant interaction between cancer cells and their surrounding microenvironment. Non-malignant cell types within this microenvironment can be reprogrammed by cancer cells to perform functions that are otherwise poorly efficient or altogether unavailable to the tumour. To understand the mechanisms behind the cooperation between stromal and cancer cells, research has largely focused on the exchange of diffusible factors between both cell types, including growth factors (e.g.TGFE, HGF, EGF) and cytokines (e.g. CXCL12, CCL7). While biochemical communication between the tumour and the stroma is well established, here we identified a cooperative invasion mechanism of physical origin that involves a pulling force exerted by CAFs on cancer cells.

We showed that force transmission between CAFs and cancer cells is mediated by a heterophilic junction between E-cadherin expressed by cancer cells and N-cadherin expressed by CAFs. A number of studies have previously demonstrated heterophilic junctions between distinct cadherin pairs, and recent structural analysis indicates that the heterophilic E-cadherin/N-cadherin interaction has higher binding affinity than the homophilic E-cadherin/E-cadherin one. However, the role of the interaction between E-cadherin and N-cadherin in physiology and disease is virtually unexplored. This gap of knowledge might be attributable, in part, to the traditional notion that expression of distinct cadherins by adjacent tissues favours tissue segregation rather than adhesion. Here we demonstrated that, rather than mediating cell separation, an E-cadherin/N-cadherin interaction enables cancer cell adhesion, migration, and invasion. Importantly, our results establish that heterotypic junctions are not only able to transmit forces, but also to trigger mechanotransduction pathways. This finding raises the possibility that, similarly to the case of homotypic junctions, E-cadherin/N-cadherin junctions regulate signaling pathways downstream of a physical force. In this connection, an E-cadherin/N-cadherin junction between cancer cells and osteogenic cells was recently observed to promote Akt signalling, although it was not linked to the application of physical force. As opposed to the case of E-cadherin and N-cadherin, we found no evidence of P-cadherin/E-cadherin junctions. This observation is consistent with the weak binding affinity predicted by structural analysis of this interaction. Taken together, our findings highlight that small structural differences such as those found in type-I cadherins lead to a broad diversity of homophilic and heterophilic interactions with pronounced mechanical and functional consequences in cancer invasion. Besides enabling adhesion, migration, invasion and force transmission, the E-cadherin/N-cadherin junction also triggered repolarization of the CAFs so as to favour their migration away from the spheroid. Repolarization away from a cell-cell contact was first reported in the late 50’s, and it is commonly termed contact inhibition of locomotion (CIL). CIL involves transient force transmission through homophilic N-cadherin junctions, followed by cell repolarization, junction dissociation and cell repulsion. In contrast with the case of N-cadherin, force transmission through homophilic E-cadherin junctions mediates adhesion but does not trigger CIL.
Our observations show that the E-cadherin/N-cadherin junction exhibits features of both E-cadherin and N-cadherin homophilic junctions. Similarly to N-cadherin homophilic junctions, the E-cadherin/N-cadherin junction mediates repolarization so as to create a leading edge on the opposite side of the cell-cell contact. Unlike N-cadherin homophilic junctions, however, the E-cadherin/N-cadherin junction is not disrupted by force application and it enables cells to migrate collectively for several hours. Thus unlike classical CIL, our results unveil a mechanism in which the asymmetric expression of different cadherins enables cells to retain adhesion while controlling front/rear polarization of the leading cell. The E-cadherin/N-cadherin junction that we describe here is intriguing because E-cadherin and N-cadherin expressing cells are usually separated by a basement membrane. We propose that evolution has selected for functional E-cadherin/N-cadherin junctions to facilitate coordinated migration of epithelial cells and fibroblasts following wounding. As with many facets of wound healing responses, the heterotypic E-cadherin/N-cadherin junction is also exploited during tumorigenesis. Our finding that impairing the E-cadherin/N-cadherin interaction virtually abrogates cancer cell invasion highlights the potential of targeting this interaction to interfere with the dissemination of cancers that metastasize while retaining epithelial characteristics. The absence of such junctions in normal tissue makes its targeting particularly appealing.
To conclude, we show that a physical force applied through a heterophilic E-cadherin/N-cadherin junction enables the cooperative invasion of CAFs and cancer cells through a double mechanism: CAFs favour invasion of cancer cells by pulling them away from the tumour, while cancer cells further enhance their spread by polarizing CAF migration away from the tumour.

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