Rocca, G. | Search bioRxiv

bioRxiv2026

Hypoxia drives trastuzumab resistance through Rac1 pathway in HER2-positive breast cancer

Resistance to targeted therapy in HER2-positive breast cancer remains a clinical challenge, especially for patients with relapsed or metastatic disease. Particularly, persistent activation of hypoxia-inducible factor 1 (HIF-1) signalling is well documented in the context of trastuzumab and trastuzumab emtansine resistance. To achieve a deeper understanding of how HIF-1 activity modulates the response to anti-HER2 treatment, we functionally characterized a cellular model of hypoxia-induced drug resistance for HER2-positive breast cancer using shotgun proteomics. By global phosphoproteomics profiling, the Rac1 pathway was identified as one of the most enriched signalling networks under hypoxia. Furthermore, the selective Rac1 blockade with the 1A-116 small-molecule inhibitor sensitised HER2-positive cells to trastuzumab in both 2D and 3D culture systems. Altogether, our findings demonstrate that hypoxic conditions induce the resistance of HER2-positive breast cancer cells to targeted therapy and suggest the therapeutic potential of Rac1 inhibition to enhance trastuzumab efficacy. HighlightsO_LIHypoxic conditions induce trastuzumab resistance in HER2-positive breast cancer. C_LIO_LIRac1 signalling was mapped under hypoxia by phosphoproteomics profiling. C_LIO_LIRac1 inhibition sensitises HER2-positive cells to trastuzumab. C_LI

cancer biology↗

bioRxiv2024

Mechanoreceptors initiate innate immunity in response to microbial infections

How mammals mount an effective immune response against infectious agents remains an unresolved fundamental issue in biology. Here, we discovered an unforeseen two-tier mechanism of neutrophil recruitment during infections, in which mechanosensing is key to initiating innate immunity. Leveraging a skin infection model and pathogenic bacteria and fungi, we demonstrate that the early recruitment of neutrophils is mainly danger-driven and partly reminiscent of sterile inflammation. Mechanistically, neutrophil recruitment is initiated by a mechanosensor-dependent pathway, involving the activation of PIEZO1 channels. This leads to LTB4 production, which, along with IL-1, induces the release of CXCL1, promoting neutrophil arrival to the site of infection. In contrast, later neutrophil recruitment is TLR- and CXCL2-dependent, highlighting a shift towards a pathogen-driven response to sustain inflammation. These findings advance our understanding of innate immunity by uncovering that mechanical and biochemical signals integrate into a circuit that initiates innate immune responses to microbial infections.

immunology↗