Crosstalk between integrin signaling and NAD⁺ biosynthetic pathways promotes glycolysis, proliferation, survival, and tumor growth in triple-negative breast cancer

Authors

• Orion Spellecy, University of Kentucky College of Medicine
• Javeria Qadir, Sunnybrook Research Institute
• Rongbo Han, University of Kentucky College of Medicine
• Kai Zhu, Shanghai Ocean University
• Bingwei Xu, University of Kentucky College of Medicine
• Yang Zhang, University of Kentucky College of Medicine
• Isha Aryal, University of Kentucky College of Medicine
• Ruei Lung Lin, University of Kentucky College of MedicineFollow
• An Hsuan Lin, University of Kentucky College of Medicine
• Abu Saleh Mosa Faisal, University of Kentucky College of Medicine
• Dana Napier, University of Kentucky College of MedicineFollow
• Dava Piecoro, University of KentuckyFollow
• Tim Scott, University of Kentucky College of Medicine
• Penghui Lin, University of Kentucky College of MedicineFollow
• Li Chen, University of Kentucky College of MedicineFollow
• Lawrence D. Brewer, University of Kentucky College of MedicineFollow
• Chi Wang, University of KentuckyFollow
• Natasha Kyprianou, Icahn School of Medicine at Mount Sinai
• Zhenheng Guo, University of KentuckyFollow
• Ruihua Guo, Shanghai Ocean UniversityFollow
• Olivier Thibault, University of KentuckyFollow
• Burton B. Yang, Sunnybrook Research InstituteFollow
• Xiuwei H. Yang, University of KentuckyFollow

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited therapeutic options. Here, we investigated how integrin-dependent signaling pathways regulate tumor metabolism and therapeutic vulnerability in TNBC. Pharmacological inhibition of the integrin/FAK axis and/or BRD4 induced cell cycle arrest, autophagy, and senescence in highly proliferative cells, consistent with a metabolic stress phenotype. Metabolomic analyses using [U-¹³C]-glucose revealed a marked suppression of glycolytic carbon flux, accompanied by an approximately 30-47% reduction in intracellular NAD⁺ levels and coordinated alterations in NADH and tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate. Mechanistically, we identified nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ biosynthesis, as a central metabolic node integrating signaling/function of the two axes. NAMPT expression/activity was sustained transcriptionally or post-translationally, including sirtuin-associated deacetylation and neddylation-dependent proteasomal turnover. In BRCA1/2-deficient TNBC, integrin-FAK and NAMPT/NAD⁺ pathways converged on Wnt/β-catenin signaling to regulate DNA repair, and response to PARP1/2 inhibitors. Co-inhibiting FAK and NAMPT synergistically suppressed tumor growth by approximately 80%. Elevated stromal NAMPT expression was associated with a trend toward favorable clinical outcomes. Collectively, these findings uncover a previously unrecognized crosstalk between integrin/FAK and NAMPT/NAD⁺ pathways in TNBC and identify a synthetic lethal–like therapeutic vulnerability that warrants further evaluation in clinically relevant models.

Document Type

Article

Publication Date

7-1-2026

Notes/Citation Information

Publisher Copyright: © The Author(s) 2026.

Digital Object Identifier (DOI)

10.1038/s41388-026-03780-2

Archival?

Archival

Repository Citation

Spellecy, Orion; Qadir, Javeria; Han, Rongbo; Zhu, Kai; Xu, Bingwei; Zhang, Yang; Aryal, Isha; Lin, Ruei Lung; Lin, An Hsuan; Faisal, Abu Saleh Mosa; Napier, Dana; Piecoro, Dava; Scott, Tim; Lin, Penghui; Chen, Li; Brewer, Lawrence D.; Wang, Chi; Kyprianou, Natasha; Guo, Zhenheng; Guo, Ruihua; Thibault, Olivier; Yang, Burton B.; and Yang, Xiuwei H., "Crosstalk between integrin signaling and NAD⁺ biosynthetic pathways promotes glycolysis, proliferation, survival, and tumor growth in triple-negative breast cancer" (2026). Markey Cancer Center Faculty Publications. 504.
https://uknowledge.uky.edu/markey_facpub/504