Lipid Metabolic Reprogramming Extends beyond Histologic Tumor Demarcations in Operable Human Pancreatic Cancer

Juho Pirhonen, Ábel Szkalisity, Jaana Hagström, Yonghyo Kim, Ede Migh, Mária Kovács, Maarit Hölttä, Johan Peränen, Hanna Seppänen, Caj Haglund, Jeovanis Gil, Melinda Rezeli, Johan Malm, Peter Horvath, György Markó-Varga, Pauli Puolakkainen, Elina Ikonen

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies and potentially curable only with radical surgical resection at early stages. The tumor microenvironment has been shown to be central to the development and progression of PDAC.A better understanding of how early human PDAC metabolically communicates with its environment and differs from healthy pancreas could help improve PDAC diagnosis and treatment. Here we performed deep proteomic analyses from diagnostic specimens of operable, treatment-naive PDAC patients (n 14), isolating four tissue compartments by laser-capture microdissection: PDAC lesions, tumor-adjacent but morphologically benign exocrine glands, and connective tissues neighboring each of these compartments. Protein and pathway levels were compared between compartments and with control pancreatic proteomes. Selected targets were studied immunohistochemically in the 14 patients and in additional tumor microarrays, and lipid deposition was assessed by nonlinear label-free imaging (n = 16). Widespread downregulation of pancreatic secretory functions was observed, which was paralleled by high cholesterol biosynthetic activity without prominent lipid storage in the neoplastic cells. Stromal compartments harbored ample blood apolipoproteins, indicating abundant microvasculature at the time of tumor removal. The features best differentiating the tumor-adjacent exocrine tissue from healthy control pancreas were defined by upregulation of proteins related to lipid transport. Importantly, histologically benign exocrine regions harbored the most significant prognostic pathways, with proteins involved in lipid transport and metabolism, such as neutral cholesteryl ester hydrolase 1, associating with shorter survival. In conclusion, this study reveals prognostic molecular changes in the exocrine tissue neighboring pancreatic cancer and identifies enhanced lipid transport and metabolism as its defining features.

Original languageEnglish
Pages (from-to)3932-3949
Number of pages18
JournalCancer Research
Volume82
Issue number21
DOIs
Publication statusPublished - 2022 Nov 1

Bibliographical note

Funding Information:
Á Szkalisity reports grants from the Magnus Ehrnrooth Foundation during the conduct of the study. E. Ikonen reports grants from the Academy of Finland, the Sigrid Juselius Foundation, Fondation Leducq, and Jane and Aatos Erkko Foundation during the conduct of the study. No disclosures were reported by the other authors.

Funding Information:
National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC). This study was supported by the Academy of Finland (307415 and 324929 to E. Ikonen), University of Helsinki (HiLIFE Fellowship and Centre of Excellence matching funds, E. Ikonen), Sigrid Juselius Foundation (E. Ikonen and H. Seppänen), Fondation Leducq (E. Ikonen), Jane and Aatos Erkko Foundation (E. Ikonen), Emil Aaltonen Foundation (J. Pirhonen), Orion Research Foundation (J. Pirhonen), Ida Montin’s Foundation (J. Pirhonen), Magnus Ehrnrooth Foundation (Á. Szkalisity), Cancer Foundation Finland (H. Seppänen and J. Pirhonen), Helsinki University Hospital Research Funds (P. Puolakkainen and H. Seppänen), Mary and Georg Ehrnrooth Foundation (H. Seppänen), LENDULET-BIOMAG Grant (2018-342 to P. Horvath), European Regional Development Funds (GINOP-2.3.2-15201600006, GINOP-2.3.215201600026, GINOP-2.3.2-152016-00037 to P. Horvath), H2020 (ERAPERMED-COMPASS, DiscovAIR; to P. Horvath), Chan Zuckerberg Initiative (Deep Visual Proteomics;

Publisher Copyright:
© 2022 American Association for Cancer Research.

Subject classification (UKÄ)

  • Cancer and Oncology

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