CD73 controls Myosin II-driven invasion, metastasis, and immunosuppression in amoeboid pancreatic cancer cells.
Remi SamainOscar MaiquesJoanne MongerHoyin LamJuliana CandidoSamantha GeorgeNicola FerrariLeonie KohIhammerSophia LunettoAdrian VarelaJose L OrgazFelip VilardellJorge Juan OlsinaXavier M GuiuDebashis SarkerAdrian BiddleFrances R BalkwillJim EylesRobert W WilkinsonHemant Mahendrakumar KocherFernando CalvoClaire M WellsVictoria Sanz-MorenoPublished in: Science advances (2023)
Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK-Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA-ROCK-Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73-ROCK-Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.
Keyphrases
- poor prognosis
- induced apoptosis
- cell cycle arrest
- long non coding rna
- genome wide
- small cell lung cancer
- squamous cell carcinoma
- binding protein
- stem cells
- endoplasmic reticulum stress
- end stage renal disease
- chronic kidney disease
- gene expression
- transcription factor
- newly diagnosed
- cell proliferation
- cell death
- mouse model
- dna methylation
- cell migration
- drug delivery
- pi k akt
- photodynamic therapy
- copy number
- patient reported outcomes
- circulating tumor cells
- prognostic factors
- induced pluripotent stem cells