Upregulated Matrisomal Proteins and Extracellular Matrix Mechanosignaling Underlie Obesity-Associated Promotion of Pancreatic Ductal Adenocarcinoma

Richard T Waldron; Aurelia Lugea; Hui-Hua Chang; Hsin-Yuan Su; Crystal Quiros; Michael S Lewis; Mingtian Che; V Krishnan Ramanujan; Enrique Rozengurt; Guido Eibl; Stephen J Pandol

doi:10.3390/cancers16081593

Upregulated Matrisomal Proteins and Extracellular Matrix Mechanosignaling Underlie Obesity-Associated Promotion of Pancreatic Ductal Adenocarcinoma

Cancers (Basel). 2024 Apr 21;16(8):1593. doi: 10.3390/cancers16081593.

Authors

Richard T Waldron^{1

2}, Aurelia Lugea^{1

2

3}, Hui-Hua Chang², Hsin-Yuan Su¹, Crystal Quiros¹, Michael S Lewis⁴, Mingtian Che⁵, V Krishnan Ramanujan⁵, Enrique Rozengurt², Guido Eibl⁶, Stephen J Pandol^{1

2

3}

Affiliations

¹ Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
³ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁴ Department of Medicine and Department of Pathology & Laboratory Medicine, VA Greater Los Angeles Health System, Cedars-Sinai Medical Center, Los Angeles, CA 90073, USA.
⁵ Biobank and Research Pathology Resource, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

Abstract

Diet-induced obesity (DIO) promotes pancreatic ductal adenocarcinoma (PDAC) in mice expressing KRasG12D in the pancreas (KC mice), but the precise mechanisms remain unclear. Here, we performed multiplex quantitative proteomic and phosphoproteomic analysis by liquid chromatography-tandem mass spectrometry and further bioinformatic and spatial analysis of pancreas tissues from control-fed versus DIO KC mice after 3, 6, and 9 months. Normal pancreatic parenchyma and associated proteins were steadily eliminated and the novel proteins, phosphoproteins, and signaling pathways associated with PDAC tumorigenesis increased until 6 months, when most males exhibited cancer, but females did not. Differentially expressed proteins and phosphoproteins induced by DIO revealed the crucial functional role of matrisomal proteins, which implies the roles of upstream regulation by TGFβ, extracellular matrix-receptor signaling to downstream PI3K-Akt-mTOR-, MAPK-, and Yap/Taz activation, and crucial effects in the tumor microenvironment such as metabolic alterations and signaling crosstalk between immune cells, cancer-associated fibroblasts (CAFs), and tumor cells. Staining tissues from KC mice localized the expression of several prognostic PDAC biomarkers and elucidated tumorigenic features, such as robust macrophage infiltration, acinar-ductal metaplasia, mucinous PanIN, distinct nonmucinous atypical flat lesions (AFLs) surrounded by smooth muscle actin-positive CAFs, invasive tumors with epithelial-mesenchymal transition arising close to AFLs, and expanding deserted areas by 9 months. We next used Nanostring GeoMX to characterize the early spatial distribution of specific immune cell subtypes in distinct normal, stromal, and PanIN areas. Taken together, these data richly contextualize DIO promotion of Kras-driven PDAC tumorigenesis and provide many novel insights into the signaling pathways and processes involved.

Keywords: KC mice; atypical flat lesions; diet-induced obesity; extracellular matrix; matrisomal proteins; pancreatic ductal adenocarcinoma; prognostic biomarkers; quantitative proteomic analysis; tandem mass tags; tumor microenvironment.

Grants and funding

1P01CA236585-01A1/NH/NIH HHS/United States