PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability

• Published in: Cancer discovery Vol. 11; no. 7; p. 1774
• Main Authors: Pitarresi, Jason R, Norgard, Robert J, Chiarella, Anna M, Suzuki, Kensuke, Bakir, Basil, Sahu, Varun, Li, Jinyang, Zhao, Jun, Marchand, Benoît, Wengyn, Maximilian D, Hsieh, Antony, Kim, Il-Kyu, Zhang, Amy, Sellin, Karine, Lee, Vivian, Takano, Shigetsugu, Miyahara, Yoji, Ohtsuka, Masayuki, Maitra, Anirban, Notta, Faiyaz, Kremer, Richard, Stanger, Ben Z, Rustgi, Anil K
• Format: Journal Article
• Language: English
• Published: United States 01-07-2021
• Subjects: Animals; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Neoplasm Metastasis; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Parathyroid Hormone-Related Protein - antagonists & inhibitors; Parathyroid Hormone-Related Protein - genetics; Parathyroid Hormone-Related Protein - metabolism
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.cd-20-1098

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
) is frequently amplified as part of the
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.
, 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. SIGNIFICANCE: Pancreatic cancer often presents with metastases, yet no strategies exist to pharmacologically inhibit this process. Herein, we establish the oncogenic and prometastatic roles of
, a novel amplified gene in pancreatic ductal adenocarcinoma. We demonstrate that blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice.
.