Spatial collagen stiffening promotes collective breast cancer cell invasion by reinforcing extracellular matrix alignment

Abstract

The tumor micro-environment often contains stiff and irregular-bundled collagen fibers that are used by tumor cells to disseminate. It is still unclear how and to what extent, extracellular matrix (ECM) stiffness versus ECM bundle size and alignment dictate cancer cell invasion. Here, we have uncoupled Collagen-I bundling from stiffness by introducing inter-collagen crosslinks, combined with temperature induced aggregation of collagen bundling. Using organotypic models from mouse invasive ductal and invasive lobular breast cancers, we show that increased collagen bundling in 3D induces a generic increase in breast cancer invasion that is independent of migration mode. However, systemic collagen stiffening using advanced glycation end product (AGE) crosslinking prevents collective invasion, while leaving single cell invasion unaffected. Collective invasion into collagen matrices by ductal breast cancer cells depends on Lysyl oxidase-like 3 (Loxl3), a factor produced by tumor cells that reinforces local collagen stiffness. Finally, we present clinical evidence that collectively invading cancer cells at the invasive front of ductal breast carcinoma upregulate LOXL3. By uncoupling the mechanical, chemical, and structural cues that control invasion of breast cancer in three dimensions, our data reveal that spatial control over stiffness and bundling underlie collective dissemination of ductal-type breast cancers.

Force Transmission in Disordered Fibre Networks

“…These findings may be relevant for cell and tissue morphology and collective cell migration in environments of different rigidity. Indeed, our results are consistent with various experimental studies, which have reported that the distance over which cells can communicate mechanically appears to depend on the stiffness of the matrix ( Guo et al, 2006 ; Reinhart-King et al, 2008 ; Winer et al, 2009 ; Janmey and Miller, 2011 ; Koorman et al, 2022 ). Furthermore, we speculate that the appearance of a characteristic transmission length that emerges around the cell when local stiffness increases may be related to the observation that cells in a colony organise at a typical distance from each other ( Reinhardt-King et al, 2008 ).…”

Role of extracellular matrix architecture and signaling in melanoma therapeutic resistance

“…Several other studies support these findings, as aligned matrices were shown to promote carcinoma, pancreatic cancer and ovarian cancer cell elongation and invasion (87,119,120). Furthermore, ECM fiber alignment and stiffness have been reported to be critical for breast cancer invasion, which is reviewed in detail by Kai et al, 2019 (102,(121)(122)(123). Surprisingly in contrast to these studies, experiments using varying ECM stiffness models, suggested that the correlation between melanoma cell invasion and substrate stiffness might differ to what was observed for other cancer models.…”

Chromatin accessibility landscape and active transcription factors in primary human invasive lobular and ductal breast carcinomas

“…3 C). Consistently, EGR1 mRNA is upregulated in ILCs [ 33 ] and TEAD increases the expression of nuclear Yes-associated protein (YAP), a transcription coactivator playing a role in cell proliferation and invasion in ILCs [ 34 , 35 ]. However, other TFs have not been studied in the context of ILCs and IDCs.…”