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Background <p>Cholesterol metabolic reprogramming plays a key role in pancreatic cancer progression by regulating the tumor immune microenvironment (TIME) and influencing responses to immunotherapy. Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), a malignancy that commonly occurs in individuals with high BMI and type 2 diabetes mellitus (T2DM). Key metabolic markers (SOAT1 and SREBP2), the tumor suppressor P53, and the immune marker CD8 are implicated in PanIN initiation, PDAC progression, and subsequent metastasis, but their associations—particularly for those that are potentially targetable—remain poorly defined.</p> Methods <p>Using publicly available PDAC datasets from the GEO database, we conducted in silico analyses to investigate the genes of interest. Additionally, we used laser capture microdissection to isolate specific cells from pancreatic cancer tissues obtained from patients. We performed translational research using 17 tumor samples, as well as 17 microdissected PanIN lesions and matched normal tissues. Protein expression analysis was further conducted on a larger cohort, including 65 PanIN lesions and 157 tumor tissues from PDAC patients.</p> Results <p>Our data identify a dual-direction expression pattern in obese and diabetic patients, with elevated levels of SOAT1, SREBP2, and P53, and reduced CD8 expression, suggesting a coordinated metabolic and immunological alteration in pancreatic cancer. High BMI and T2DM, recognized as independent risk factors for PDAC, are significantly associated with dysregulation of key markers involved in the mevalonate pathway and the TIME, potentially contributing to PanIN and PDAC progression.</p> Conclusion <p>These findings warrant further longitudinal and mechanistic studies to clarify whether metabolic modulation may influence PDAC risk or clinical outcomes.</p> Graphical abstract <p></p>

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Obesity and diabetes associated with dysregulation of mevalonate pathway markers and progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Fereshteh Rezagholizadeh,
  • Sara Rokn,
  • Mohammadhossein FakherBaheri,
  • Zahra Taherian,
  • Hossein Rostami,
  • Farid Azmoudeh-Ardalan,
  • Mandana Rahimi,
  • Masoud Baghai Wadji,
  • Atefeh Kashanizadeh,
  • Sanaz Eghtedari,
  • Alireza Lotfalizadeh,
  • Ali Sharifi-Zarchi,
  • Elahe Safari,
  • Mohammad Taghi Joghataei

摘要

Background

Cholesterol metabolic reprogramming plays a key role in pancreatic cancer progression by regulating the tumor immune microenvironment (TIME) and influencing responses to immunotherapy. Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), a malignancy that commonly occurs in individuals with high BMI and type 2 diabetes mellitus (T2DM). Key metabolic markers (SOAT1 and SREBP2), the tumor suppressor P53, and the immune marker CD8 are implicated in PanIN initiation, PDAC progression, and subsequent metastasis, but their associations—particularly for those that are potentially targetable—remain poorly defined.

Methods

Using publicly available PDAC datasets from the GEO database, we conducted in silico analyses to investigate the genes of interest. Additionally, we used laser capture microdissection to isolate specific cells from pancreatic cancer tissues obtained from patients. We performed translational research using 17 tumor samples, as well as 17 microdissected PanIN lesions and matched normal tissues. Protein expression analysis was further conducted on a larger cohort, including 65 PanIN lesions and 157 tumor tissues from PDAC patients.

Results

Our data identify a dual-direction expression pattern in obese and diabetic patients, with elevated levels of SOAT1, SREBP2, and P53, and reduced CD8 expression, suggesting a coordinated metabolic and immunological alteration in pancreatic cancer. High BMI and T2DM, recognized as independent risk factors for PDAC, are significantly associated with dysregulation of key markers involved in the mevalonate pathway and the TIME, potentially contributing to PanIN and PDAC progression.

Conclusion

These findings warrant further longitudinal and mechanistic studies to clarify whether metabolic modulation may influence PDAC risk or clinical outcomes.

Graphical abstract