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Cholesterol: A Fork in the Road for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is predicted to surpass colorectal cancer as the second leading cause of cancer death in the US in the next decade (1). This dismal projection is largely due to late diagnosis—often after the cancer has spread to other organs. Where these cells migrate matters: patients with lung metastases tend to have better outcomes than those with liver or multisite metastases (2). Thanks to a 2022 AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grant, Rushika M. Perera, PhD and her team at the University of California, San Francisco identified a protein that plays a key role in cholesterol metabolism, PCSK9 (3), as a key predictor of whether pancreatic cancer cells colonize the liver or the lungs (4).

Rushika M. Perera, PhD

AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grants stimulate “high-risk, high-reward” research led by early-to mid-career investigators—research that might otherwise go unfunded through conventional channels. Dr. Perera, now the Deborah Cowan Professor in medicine and vice chair of the Department of Anatomy at the University of California San Francisco, set out in 2022 to investigate how the metabolic traits of PDAC cells shape their preference for secondary organs. “We were interested in determining the distinct metabolic dependencies of primary versus metastatic PDAC, recognizing that tumor growth in the pancreas, liver, or lungs is likely shaped by the unique metabolic environments of each organ,” she explained.

Her team analyzed 25 PDAC cell lines and discovered two distinct groups: one that preferentially metastasizes to the liver and another to the lungs. Surprisingly, these preferences were not explained by common genetic mutations such as KRAS, CDKN2A, or TP53. Instead, gene expression analyses revealed that PCSK9 was enriched in lung-tropic cells. PCSK9 binds to the LDL cholesterol receptor and promotes its degradation, limiting cholesterol uptake. Further studies—including patient samples—confirmed the pattern: lung metastases had high PCSK9 and low LDL receptor expression, while liver metastases showed the opposite.

The team demonstrated that liver-tropic cells depend on LDL cholesterol uptake for survival. When cultured in lipoprotein-depleted serum, these cells showed reduced proliferation—a deficit reversed by adding LDL or cholesterol. In contrast, lung-tropic cells, with low LDL receptor expression, ramped up cholesterol biosynthesis genes, a trend also observed in patient lung metastases. In short, liver metastases rely on cholesterol uptake, while lung metastases synthesize cholesterol de novo. PCSK9-LDLR status determines this metabolic strategy, influencing where pancreatic cancer cells thrive.

Cholesterol also affects cell growth through mTORC1 signaling (5). Liver-tropic cells accumulate lysosomal cholesterol, activating mTORC1, but lose this signaling when lipoproteins are unavailable. Lung-tropic cells maintain mTORC1 activity even without external cholesterol—a capability tied to PCSK9 expression. “Our findings highlight PCSK9 as a promising biomarker and suggest that differential reliance on cholesterol uptake versus biosynthesis exerts organ-specific effects on tumor growth,” said Dr. Perera. “This may offer new opportunities for tailoring anti-metastatic therapies based on the metabolic context of each target organ.”

Reflecting on her career, Dr. Perera emphasized the importance of AACR support:
“I’m grateful to have received AACR support at several pivotal stages in my career—from being named a NextGen Star during my postdoctoral training, to receiving the AACR-PanCAN Career Development Award as a junior faculty member, and later, the AACR-MPM Award as an established investigator. Each of these awards came at a critical juncture, enabling me to launch and sustain ambitious research directions.”

 References

  1. Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open.  2021; 4 (4):e214708
  2. Link JM, Eng JR, Pelz C, MacPherson-Hawthore K, Worth PJ, Sivagnanam S, et al. Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer. Nat Cancer. 2025; 6 (1):123-144
  3. Bao X, Liang Y, Chang H, Cai T, Feng B, Gordon K, et al. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal Transduct Target Ther.  2024; 9:13
  4. Rademaker G, Hernandez GA, Seo Y, Dahal S, Miller-Phillips L, Li AL, et al. PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer. Nature.  2025; 643(8074):1381-1390
  5. Castellano BM, Thelen AM, Moldavski O, Feltes M, van der Welle REN, Mydock-McGrane L, et al. Lysosomal Cholesterol Activates mTORC1 via an SLC38A9-Niemann Pick C1 Signaling Complex. Science.  2017; 355(6331):1306-1311