PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability
Abstract
Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone–related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in patients with pancreatic cancer. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in pancreatic ductal adenocarcinoma metastases. Loss of PTHrP—either genetically or pharmacologically—dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the ability of tumor cells to initiate metastatic cascade. Spp1, which encodes osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 15, 2021
- Source ID
- 10.1158/2159-8290.cd-20-1098
Entities
People
- Amy Zhang
- Anil K. Rustgi
- Anirban Maitra
- Anna M Chiarella
- Antony Hsieh
- Basil Bakir
- Ben Z Stanger
- Benoît Marchand
- Faiyaz Notta
- Il-kyu Kim
- Jason R Pitarresi
- Jinyang Li
- Jun Zhao
- Karine Sellin
- Kensuke Suzuki
- Masayuki Ohtsuka
- Maximilian D. Wengyn
- Richard Kremer
- Robert J. Norgard
- Shigetsugu Takano
- Varun Sahu
- Vivian Lee
- Yoji Miyahara
Organizations
- Canadian Institutes of Health Research
- Chiba University
- Columbia University
- McGill University
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Pennsylvania
- University of Texas at Austin
- University of Toronto