Cholesterol’s Role ‌in​ Aggressive Colon​ Tumors Identified

‍⁤ ​ updated June 16,2025
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A new preclinical study from Weill Cornell Medicine suggests that increased cholesterol production fuels the growth of hard-to-detect,pre-cancerous colorectal ⁢lesions,known as serrated polyps,and the aggressive tumors that stem from them. The findings ‌highlight the potential of ⁤using ⁢cholesterol-lowering drugs for both preventing and ⁢treating ‌these tumors.

The research, which examined mice with serrated polyps ‍and‌ tumors, detailed the molecular events leading to​ elevated cholesterol production in these tissues. the team then validated these findings through analyses of human serrated ‍polyps and tumors. Further experiments in mouse models showed that‍ blocking cholesterol production effectively halted the progression of these intestinal tumors.

Dr. Jorge Moscat, co-senior author and Homer T. Hirst III Professor of Oncology in Pathology at Weill‍ Cornell Medicine, noted the meaning of the revelation. “Serrated-type polyps and ‌tumors currently are ⁣not treated⁣ differently from othre colorectal neoplasias,but ⁤as ⁣our work ⁢shows,they have this specific metabolic vulnerability‌ that⁤ can be targeted,” Moscat said.

While cholesterol has been considered a pro-growth molecule, its direct ​link to⁤ colorectal cancer prevention has‍ been unclear. Prior studies​ yielded conflicting results regarding the ​effectiveness⁤ of statins ⁣in preventing colorectal cancers.

Dr. Maria ‍Diaz-Meco, also ⁢a co-senior author and Homer T. Hirst III Professor of Oncology in Pathology ⁢at Weill Cornell Medicine, explained the nuanced impact‌ of cholesterol-lowering interventions. “Trials of statins to prevent colorectal cancer‌ have had conflicting results,”​ Diaz-Meco said. “Our ⁤findings suggest that​ this is because targeting ⁣cholesterol has a preventive but selective effect only against ​polyps and tumors of this serrated type.”

serrated polyps, characterized ‍by their sawtooth appearance, are⁤ often overlooked during ​colonoscopies due⁢ to ​their flat‌ shape. Tumors​ developing from these polyps account for ‍15‍ to 30 percent‍ of colorectal cancers and contain⁢ highly⁢ invasive, treatment-resistant ​cells.

The research team previously ‍linked serrated ​polyps‌ and tumors ​to low levels of​ aPKC enzymes. Mice​ lacking‍ these enzymes ‌in⁤ their gut linings consistently⁣ developed serrated polyps and aggressive tumors. The current study revealed that cholesterol synthesis was significantly‍ upregulated‌ in serrated-type tumors,suggesting its role as an early driver of tumor development.

Researchers found that the absence of aPKC enzymes activated a ‌transcription factor called SREBP2,⁢ which in turn⁢ boosted cholesterol production. tests ⁢on human colorectal polyp and tumor​ samples corroborated these findings, showing that⁤ only ​serrated-type tumors exhibited⁣ low aPKC levels alongside ⁤SREBP2 accumulation.

The team tested a combination of cholesterol synthesis-blocking drugs, ​including atorvastatin, on young mice with⁣ low aPKC⁢ levels. This treatment significantly reduced the formation rate‌ of‍ both serrated⁢ polyps and tumors. The tumors that⁣ did develop were also less aggressive.

What’s next

The Moscat and Diaz-Meco labs are planning a clinical‌ trial to assess cholesterol-lowering interventions in ‍patients who⁤ have⁢ had serrated colorectal polyps removed, aiming ‍to prevent the recurrence‌ of this aggressive cancer type.