Berquand, A. | bioRxiv Science

bioRxiv2026

LRP-1 promotes tumor progression of triple negative breast cancers by coordinating extracellular matrix remodeling and immune cell infiltration

Structural AbstractO_ST_ABSBackgroundC_ST_ABSTriple-negative breast cancer (TNBC) represents a major clinical challenge due to its aggressiveness, heterogeneity and limited availability of effective targeted therapy. We investigated whether LRP-1, a multifunctional cell-surface endocytic and signaling receptor, contributes to TNBC progression. MethodsUsing CRISPR-Cas9, LRP-1-deficient murine 4T1 and human HS578-T TNBC cells were used. Functional consequences were assessed through migration, invasion, and 3D spheroid assays, imaging of focal adhesions and actin organization, atomic force microscopy, and plasmin activity assays. Global molecular reprogramming was analyzed by label-free quantitative proteomics and secretomics. LRP-1-deficient or proficient 4T1 cells were implanted orthotopically in immunocompetent mice; tumor progression was monitored longitudinally while peritumoral collagen architecture and immune microenvironment composition were characterized by second harmonic generation imaging and immunohistochemistry. ResultsWe show that LRP-1 loss reduces TNBC aggressiveness, as reflected by decreased migration and invasive capacity, reduced spheroid evasion, and significant morphological changes in focal adhesion and actin structure. LRP-1-deficient cells became stiffer and showed lower LOXL-4 levels, while pericellular proteolytic activity remained unchanged, suggesting other proteases mechanism. Multi-omic analysis revealed alterations in extracellular matrix (ECM), epithelial-mesenchymal transition, and inflammatory pathways. In vivo, LRP-1-deficiency reduced tumor progression and peritumoral collagen deposition, while increasing CD8+ T and Natural Killer cell infiltration, together with a cytokine profiling compatible with a more immune-permissive microenvironment. ConclusionsLRP-1 act as a key contributor in TNBC progression through matrix remodeling, mechano-adaptation, and immune exclusion. Positioning it as a candidate biomarker for TNBC patients who are likely to benefit from stroma-targeting therapies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/732906v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@1b595c2org.highwire.dtl.DTLVardef@7b208aorg.highwire.dtl.DTLVardef@1956e54org.highwire.dtl.DTLVardef@17e55d0_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cancer Biology↗

bioRxiv2024

Dual action of sphinganine in the plant disease resistance to bacteria.

Sphingolipids are ubiquitous, highly diverse molecules constituting at least 40% of plant plasma membranes. Initially known as modulators of membrane integrity, they now emerge as important players in plant responses to (a)biotic stresses. The interaction between Arabidopsis thaliana and the bacterium Pseudomonas syringae pv. tomato DC3000 AvrRpm1 (Pst AvrRpm1) culminates in the activation of a programmed cell death known as the hypersensitive response, which is part of the plant immune response. In this study, we showed that the co-infiltration of Pst AvrRpm1 and sphinganine (d18:0) in Arabidopsis leaves suppress the hypersensitive response. This suppression phenotype is also observed with bacteria carrying the effectors AvrB and AvrPphB but not with the ones carrying AvrRpt2 and AvrRps4. Sphingolipid-induced hypersensitive response suppression by Pst AvrRpm1 is correlated with the down-regulation of the gene AtNMT1 encoding a N-myristoyltransferase. d18:0 does not have a direct antibacterial effect and its co-infiltration in plants does not display typical signs of immune response such as activation of salicylic acid signaling pathway and extracellular reactive oxygen species production. Biophysical studies showed that d18:0 interacts with plant plasma membrane lipids. More specifically, d18:0 disturbs plant plasma membrane organization and mechanical properties. Our results demonstrate that sphingolipids play an important role in plant resistance, especially by interfering with the plasma membrane organization and effector localization and thus disturbing their function and subsequent immune responses.

plant biology↗