Bellinzona – June 14 2024 – Despite the established roles of both HMGB1 and CXCL12 in tumour progression and metastatic spread to distal sites, the role of the CXCL12/HMGB1 heterocomplex in cancer has never been investigated.
In the study, published in Frontiers in Immunology by Pirani et al., a new mass spectrometry protocol was established to unambiguously distinguish reduced and oxidized HMGB1 isoforms in cell lysates. Human epithelial cells derived from breast and prostate cancer predominantly express HMGB1 in its reduced form, allowing the formation of CXCL12/HMGB1 heterocomplex. All cancer cells release HMGB1 in the extracellular microenvironment together with varying concentrations of thioredoxin and thioredoxin reductase. The CXCL12/HMGB1 heterocomplex enhances, via CXCR4, the directional migration and invasiveness of cancer cells characterized by high metastatic potential that possess a fully active thioredoxin system, contributing to maintain HMGB1 in its reduced form. On the contrary, cancer cells with low metastatic potential, lack thioredoxin reductase, promptly uptake CXCL12, and fail to respond to the heterocomplex.
The different responsiveness of cancer cells to the CXCL12/HMGB1 heterocomplex suggests its disruption as a potential therapeutic target to inhibit invasion and metastatic spread in cancer therapies.
This study was performed in Uguccioni’s lab in collaboration with the Bios+ Mass Spectrometry Facility (https://irb.usi.ch/facilities/mass-spectrometry/), and supported by the Swiss National Science Foundation, the San Salvatore Foundation, and the Ceschina Foundation.
