Platinum-induced upregulation of ITGA6 promotes chemoresistance and spreading in ovarian cancer.
Alice GambelliAnna NespoloGian Luca Rampioni VinciguerraEliana PivettaIlenia PellarinMilena S NicolosoChiara ScapinLinda StefenattiIlenia SegattoAndrea FaveroSara D'AndreaMaria Teresa MucignatMichele BartolettiEmilio LuciaMonica SchiappacassiPaola SpessottoVincenzo CanzonieriGiorgio GiordaFabio PuglisiAndrea VecchioneBarbara BellettiMaura SonegoGustavo BaldassarrePublished in: EMBO molecular medicine (2024)
Platinum (PT)-resistant Epithelial Ovarian Cancer (EOC) grows as a metastatic disease, disseminating in the abdomen and pelvis. Very few options are available for PT-resistant EOC patients, and little is known about how the acquisition of PT-resistance mediates the increased spreading capabilities of EOC. Here, using isogenic PT-resistant cells, genetic and pharmacological approaches, and patient-derived models, we report that Integrin α6 (ITGA6) is overexpressed by PT-resistant cells and is necessary to sustain EOC metastatic ability and adhesion-dependent PT-resistance. Using in vitro approaches, we showed that PT induces a positive loop that, by stimulating ITGA6 transcription and secretion, contributes to the formation of a pre-metastatic niche enabling EOC cells to disseminate. At molecular level, ITGA6 engagement regulates the production and availability of insulin-like growth factors (IGFs), over-stimulating the IGF1R pathway and upregulating Snail expression. In vitro data were recapitulated using in vivo models in which the targeting of ITGA6 prevents PT-resistant EOC dissemination and improves PT-activity, supporting ITGA6 as a promising druggable target for EOC patients.
Keyphrases
- induced apoptosis
- small cell lung cancer
- squamous cell carcinoma
- newly diagnosed
- cell cycle arrest
- ejection fraction
- end stage renal disease
- poor prognosis
- endoplasmic reticulum stress
- transcription factor
- cell proliferation
- cystic fibrosis
- patient reported outcomes
- adipose tissue
- escherichia coli
- electronic health record
- mouse model
- skeletal muscle
- gene expression
- single molecule
- oxidative stress
- insulin resistance
- staphylococcus aureus
- endothelial cells
- artificial intelligence