Paper link: doi.org/10.1016/j.ce...
authors.elsevier.com/c/1kEhfL7PXq...

THANK YOU Tavazoie Lab @sohailtavazoie.bsky.social, outstanding medical students Schayan and Anthea, our collaborators @lund-university.bsky.social Christopher, Karolin and Helena, @rockefelleruniv.bsky.social for the great research environment. And thank you patients for sharing the valuable data!!

PCSK9 inhibitors have been approved to lower cholesterol. We tested one developed by @amgen.bsky.social. Evolocumab suppressed breast cancer metastasis in multiple mouse models. Evaluating rs562556 as a biomarker, our collaborator found that it predicted a higher risk of metastasis (9/9)

What's downstream of PCSK9-LRP1? RNASeq analysis revealed that PCSK9 induced the expression of a set of IFN-associated pro-metastatic genes, which are suppressed by LRP1. We functionally characterized 2 of them, USP18 and XAF1, as metastatic promoters (8/9)

How does a single missense mutation on PCSK9 impact metastasis? We found that V474I may increase PCSK9’s binding to, and suppression of, tumoral LRP1. Breast cancer cells seem to be quite sensitive to LRP1 level as modest reduction of LRP1 is sufficient to drive metastasis (7/9)

PCSK9 is known to degrade membrane proteins. We searched for proteins that reduced in abundance upon PCSK9 treatment, focusing on LDLR and LRP1. Depletion of LRP1 but not LDLR abolished the effect of PCSK9. This resonates with our old paper on LRP1's suppression of metastasis (6/9)

We next studied at which step of the metastatic cascade PCSK9 has an impact. We found that PCSK9 promoted metastatic initiation in vivo. Recombinant PCSK9 treatment in vitro also increased colony initiation, bringing our focus to PCSK9's effect on cancer cells (5/9)

Initially we thought PCSK9 may drive metastasis by increasing cholesterol, as obesity is a risk factor for breast cancer relapse. But PCSK9 KO mice on high cholesterol diet, which normalized cholesterol and LDL level, continued to show reduced breast cancer metastasis (4/9)

This SNP causes a missense mutation in PCSK9 (pV474I). Genetic modeling of this gain-of-function single nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple models (3/9)

It's been thought that somatic mutations emerge during tumorigenesis and drive metastasis, the critical determinant of cancer survival. Here we found a SNP in the cholesterol homeostasis regulator PCSK9 that associates with reduced survival in multiple breast cancer cohorts (2/9)