Thanks Walter !

Thank you my friend😊

thank you! 😊

thanks John!

thank yoy!

thanks Jim !

Thank you Christian! 🙏

Thanks Gina !

We are grateful to the granting agencies, including
@theaacr.bsky.social, NIH, The Ed Mara Passion to Win Fund and the Belgian American Education Foundation (to G.R), which supported this work.

Thank you to our wonderful collaborators and their lab members - @robzonculab.bsky.social Jen Jen Yeh,
Eric Collisson, the German PDAC consortium, Mark Looney, Bruce Wang, Grace Kim, Kwun Wen - and to
@nature.com and the reviewers for their thoughtful review of our study.

These findings show that chol. uptake favors liver growth, while synthesis supports lung growth. Accordingly, PCSK9 o/e shifted liver-avid cells to the lung, while PCSK9 KO redirected lung-avid cells to the liver, establishing PCSK9 as a key regulator of metastatic organ choice

Reliance on de novo cholesterol synthesis, enables lung-avid cells to produce intermediates like 7-dehydrocholesterol that confer resistance to oxidative stress (eg, ferroptosis) in the oxygen-rich lung environment.

The ability to uptake cholesterol and route it to the lysosome, enables liver-avid cells to maintain high mTORC1 signaling and produce an oxysterol (eg, 24-hydroxycholesterol) that can activate adjacent hepatocytes to support tumor growth.

PCSK9 is a negative regulator of LDLR - the receptor for uptake of LDL-cholesterol. Accordingly, lung-avid lines which express high PCSK9 cannot uptake LDL and instead biosynthesize cholesterol, while liver-avid lines which express low PCSK9 efficiently uptake LDL-cholesterol.

To identify metabolic drivers linked to secondary organ choice, we interrogated gene expression analyses to determine which genes were differentially upregulated in lung- versus liver-avid lines. This analysis identified PCSK9 as the top ranked gene correlating with lung-avid

Gilles then validated these findings using in vivo transplant models of metastasis and showed that specific PDAC lines preferred to seed and grow in the liver while others preferred the lung. We also noted that metastatic organ preference correlates with PDAC subtype.

Our study began by interrogating the MetMap database depmap.org/metmap/ to identify organ tropic behaviors of human PDAC cell lines. We noted that several lines showed selective preference for liver colonization relative to other organs including the lung.

PDAC metastasizes to the liver, lungs, peritoneum and lymph nodes - we were interested in identifying key metabolic dependencies that enable efficient seeding the colonization in the liver and lungs.