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

Pirhonen, Juho ; Szkalisity, Ábel ; Hagström, Jaana ; Kim, Yonghyo LU ; Migh, Ede ; Kovács, Mária ; Hölttä, Maarit ; Peränen, Johan ; Seppänen, Hanna and Haglund, Caj , et al. (2022) In Cancer Research 82(21). p.3932-3949
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
82
issue
21
pages
18 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • pmid:36054547
  • scopus:85141999255
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-22-0396
language
English
LU publication?
yes
additional info
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.
id
50a3c805-a806-45b7-b456-4b015c3bd055
date added to LUP
2022-12-30 13:31:17
date last changed
2024-06-10 06:03:50
@article{50a3c805-a806-45b7-b456-4b015c3bd055,
  abstract     = {{<p>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.</p>}},
  author       = {{Pirhonen, Juho and Szkalisity, Ábel and Hagström, Jaana and Kim, Yonghyo and Migh, Ede and Kovács, Mária and Hölttä, Maarit and Peränen, Johan and Seppänen, Hanna and Haglund, Caj and Gil, Jeovanis and Rezeli, Melinda and Malm, Johan and Horvath, Peter and Markó-Varga, György and Puolakkainen, Pauli and Ikonen, Elina}},
  issn         = {{0008-5472}},
  language     = {{eng}},
  month        = {{11}},
  number       = {{21}},
  pages        = {{3932--3949}},
  publisher    = {{American Association for Cancer Research Inc.}},
  series       = {{Cancer Research}},
  title        = {{Lipid Metabolic Reprogramming Extends beyond Histologic Tumor Demarcations in Operable Human Pancreatic Cancer}},
  url          = {{http://dx.doi.org/10.1158/0008-5472.CAN-22-0396}},
  doi          = {{10.1158/0008-5472.CAN-22-0396}},
  volume       = {{82}},
  year         = {{2022}},
}