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Gilles Rademaker shared study in Nature on PCSK9 and organ-specific metastasis in pancreatic cancer

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May 24, 2025, 19:08

Gilles Rademaker shared study in Nature on PCSK9 and organ-specific metastasis in pancreatic cancer

Gilles Rademaker, Research Fellow at the University of Liège, shared a LinkedIn post about his recent study published in Nature:

“I am super excited to share that my postdoc paper is now online in Nature!

This study is the result of years of hard work and incredible collaborations, and I am very proud to see it published.

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver and lungs, but what determines this organ-specific preference?

Using in vivo transplant models, we showed that different PDAC lines have distinct preferences for colonizing either the liver or the lung and that this correlates with PDAC transcriptional subtype.

To uncover the metabolic drivers behind this organotropism, we performed transcriptomic analyses and identified PCSK9 as the top gene associated with lung-avid PDAC lines.

PCSK9 is a negative regulator of LDLR, the receptor responsible for LDL-cholesterol uptake. Its expression defines how PDAC cells access cholesterol:

– Lung-avid cells express high PCSK9, resulting in low LDLR levels and reduced LDL uptake. These cells compensate by upregulating cholesterol biosynthesis and accumulate intermediates like 7-dehydrocholesterol and 7-dehydrodesmosterol, which protect against oxidative stress in the oxygen-rich lung environment.

– Liver-avid cells, by contrast, express low PCSK9 and maintain high LDLR levels, enabling efficient LDL uptake. This supports mTORC1 signaling and leads to the production of an oxysterol namely 24-hydroxycholesterol, which activates hepatocytes and help create a pro-metastatic niche in the liver.
Functionally, modulating PCSK9 expression was sufficient to change metastatic destination:

– Overexpressing PCSK9 redirected liver-avid cells to the lung.

– Knocking out PCSK9 enabled lung-avid cells to grow in the liver.

These results identify PCSK9 as a key metabolic regulator of organ-specific metastasis in pancreatic cancer.

I’m incredibly grateful to my mentor Rushika Perera, our collaborators and co-authors for their support and insight, and to my funding sources for making this work possible.”

Title: PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer

Journal: Nature Portfolio

Authors: Gilles Rademaker, Grace A. Hernandez, Yurim Seo, Sumena Dahal, Lisa Miller-Phillips, Alexander L. Li, Xianlu Laura Peng, Changfei Luan, Longhui Qiu, Maude A. Liegeois, Bruce Wang, Kwun W. Wen, Grace E. Kim, Eric A. Collisson, Stephan F. Kruger, Stefan Boeck, Steffen Ormanns, Michael Guenther, Volker Heinemann, Michael Haas, Mark R. Looney, Jen Jen Yeh, Roberto Zoncu, Rushika M. Perera

Read the full article.

pancreatic cancer

Learn more about pancreatic cancer on OncoDaily.

Alexander L. Li Bruce Wang cancer Changfei Luan Eric A. Collisson Gilles Rademaker Grace A. Hernandez Grace E. Kim Jen Jen Yeh Kwun W. Wen Lisa Miller-Phillips Longhui Qiu Mark R. Looney Maude A. Liegeois Michael Guenther Michael Haas Nature OncoDaily Oncology Pancreatic Cancer pancreatic ductal adenocarcinoma PCSK9 PDAC Roberto Zoncu Rushika M. Perera Stefan Boeck Steffen Ormanns Stephan F. Kruger Sumena Dahal University of Liege Volker Heinemann Xianlu Laura Peng Yurim Seo

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