2. Academic Validation
  3. The Prolyl Isomerase PIN1 Impacts Fibroblast Differentiation States and Crosstalk in Pancreatic Cancer

The Prolyl Isomerase PIN1 Impacts Fibroblast Differentiation States and Crosstalk in Pancreatic Cancer

  • Cancer Res. 2025 Sep 18. doi: 10.1158/0008-5472.CAN-24-3437.
Chloe L Bowman 1,  Colin J Daniel 2,  Eric J Carlson 3,  Vidhi M Shah 3,  Amy S Farrell 4,  Kayleigh M Kresse 3,  Xiaoyan Wang 4,  Kyra A Lindley 2,  Madeline R Kuhn 2,  Kevin MacPherson-Hawthorne 3,  Brittany L Allen-Petersen 5,  Jennifer Eng 6,  Motoyuki Tsuda 3,  Isabel A English 2,  Carl Pelz 2,  Arslan Amer 2,  Aaron R Doe 2,  Megan A Turnidge 3,  Zina P Jenny 4,  Trent Waugh 7,  Zinab O Doha 8,  Nicholas D Kendsersky 4,  Kristof Torkenczy 3,  Katherine R Pelz 9,  Andrew J Fields 3,  Gabriel M Cohn 3,  Gabrielle S Dewson 3,  Mary C Thoma 3,  Taylor S Amery 3,  Mara H Sherman 10,  Koei Chin 11,  Anupriya Agarwal 4,  Jason M Link 12,  Brett C Sheppard 2,  Andrew C Adey 4,  Rosalie C Sears 4,  Ellen M Langer 2
Affiliations

Affiliations

  • 1 Oregon Health & Science University, Oregon, United States.
  • 2 Oregon Health & Science University, Portland, OR, United States.
  • 3 Oregon Health & Science University, United States.
  • 4 Oregon Health & Science University, Portland, Oregon, United States.
  • 5 Purdue University West Lafayette, West Lafayette, Indiana, United States.
  • 6 Oregon Health and Sciences University, Portland, United States.
  • 7 Oregon Health and Sciences University, Portland, Oregon, United States.
  • 8 Taibah University, Madina, Saudi Arabia.
  • 9 Oregon Health & Science University, Portland, OREGON, United States.
  • 10 Memorial Sloan Kettering Cancer Center, New York, United States.
  • 11 Oregon Health and Science University, Portland, OR, United States.
  • 12 University of California, Los Angeles, Los Angeles, United States.
PMID: 40966318 DOI: 10.1158/0008-5472.CAN-24-3437
Abstract

The prolyl isomerase PIN1 is overexpressed in Cancer and contributes to Cancer cell-intrinsic phenotypes including proliferation and migration. However, PIN1 may also function in stromal cells within the tumor microenvironment (TME). Here, we showed that PIN1 is a critical regulator of pancreatic stellate cell (PSC) state at baseline and in response to the myofibroblast activating factor TGF-β. Loss or inhibition of PIN1 altered the epigenetic and transcriptional response of PSCs to TGF-β, preventing PSC differentiation to a myofibroblast state and altering expression of secreted matrix proteins and signaling molecules. Consistent with inhibition of the TGF-β response, low fibroblast PIN1 expression in mouse and human pancreatic ductal adenocarcinoma (PDAC) correlated with low expression of α-SMA, a marker of myofibroblast activation. Decreased PIN1 expression at baseline also altered paracrine HGF signaling from fibroblasts to tumor cells. PSCs with low PIN1 expression displayed reduced expression and secretion of HGF, resulting in an attenuation of c-MET receptor phosphorylation and signaling in nearby Cancer cells. In allograft models, host PIN1 was critical for normal growth of a subset of pancreatic Cancer cell lines that are responsive to HGF signaling. Through the identification of changes to fibroblast activation state and crosstalk following PIN1 loss or inhibition, these data suggest that systemic targeting of PIN1 will suppress the pro-tumorigenic PDAC microenvironment and may differentially affect heterogeneous patient populations.

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