Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity.

Abstract

BACKGROUND:

Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs.

METHODS:

We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers.

RESULTS:

Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment.

CONCLUSIONS:

The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes. A Schematic illustration of the role of NR5A2 in cancer stem cells versus differentiated cancer cells, along with the action of the NR5A2 inhibitor Cpd3. B Overall survival of tumor-bearing mice following allocated treatment. A total of 18 PDX models were treated using a 2 x 1 x 1 approach (two animals per model per treatment); n=36 per group (illustration created with biorender.com ).

• Authors: Quan Zheng, Jiajia Tang, Alexandra Aicher, Tony Bou Kheir, Berina Sabanovic, Preeta Ananthanarayanan, Chiara Reina, Minchun Chen, Jian-Min Gu, Bin He, Sonia Alcala, Diana Behrens, Rita T Lawlo, Aldo Scarpa, Manuel Hidalgo, Bruno Sainz Jr, Patricia Sancho, Christopher Heeschen
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 42 Issue 1 Pg. 323 (Nov 28 2023) ISSN: 1756-9966 [Electronic] England
• PMID: 38012687 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• Proto-Oncogene Proteins c-myc
• NR5A2 protein, human
• Receptors, Cytoplasmic and Nuclear
• SOX2 protein, human
• SOXB1 Transcription Factors

Topics

• Humans
• Animals
• Mice
• Signal Transduction
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Cell Line, Tumor
• Neoplasm Recurrence, Local (pathology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, metabolism)
• Neoplastic Stem Cells (metabolism)
• Receptors, Cytoplasmic and Nuclear (metabolism)
• SOXB1 Transcription Factors (genetics, metabolism)