Elevated TRPP2 promotes malignant behavior of head and neck cancer via enhancing exosome biogenesis

Exosomes promote cancer progression by mediating intercellular communication via oncogenic cargos. These vesicles originate as intraluminal vesicles (ILVs) within multivesicular bodies (MVBs), with their secretion dependent on MVB trafficking. The endosomal sorting complex required for transport (ESCRT) complex plays a key role in sorting proteins into exosomes, while the calcium channel Transient Receptor Potential Polycystin-2 (TRPP2) may regulate exosome biogenesis and amplify their oncogenic potential. In this study, we analyzed TRPP2 level in HNC tissues using immunohistochemistry (IHC) and correlated them with clinical outcomes via UALCAN data. We characterized exosomes from medium, by nanoparticle tracking analysis (NTA), transmission electron microscopy, and exosome quantification. We measured intracellular calcium levels of HNC cells using Fluo-8 AM. Additionally, protein interactions were assessed via co-immunoprecipitation (co-IP) and immunofluorescence. Functional assays included in vitro proliferation, migration, cell cycle analysis, and in vivo xenograft models. The expression of TRPP2 was significantly higher in HNC tissues, correlating with advanced tumor stages and poor prognosis. Knockdown of TRPP2 in HNC cells diminished exosome secretion by impairing MVB-Rab11a interaction, a process dependent on TRPP2-mediated calcium influx. Exosomes derived from TRPP2 overexpression cells exhibited enriched oncogenic proteins, driven by TRPP2's regulation of ESCRT subunits VPS37B and CHMP6. These exosomes enhanced HNC cell proliferation, migration, and xenograft tumor growth. Our study demonstrates that TRPP2 drives HNC malignancy via two pivotal mechanisms: calcium-dependent regulation of MVBs trafficking to enhance exosome secretion, and modulation of exosomal cargo through ESCRT components. These findings establish TRPP2 as a critical regulator of exosome biogenesis and underscore its promise as a therapeutic target for HNC. Targeted TRPP2 inhibition may disrupt tumor-stromal crosstalk, thereby improving therapeutic outcomes in HNC and other exosome-driven malignancies.