A NOTCH3-CXCL12-driven myeloma-tumor niche signaling axis promotes chemoresistance in multiple myeloma
Hayley M. Sabol,
Cody Ashby,
Manish Adhikari,
Aric Anloague,
Japneet Kaur,
Sharmin Khan,
Samrat Roy Choudhury,
Carolina Schinke,
Michela Palmieri,
C. Lowry Barnes,
Elena Ambrogini,
Intawat Nookaew,
Jesus Delgado-Calle
Affiliations
Hayley M. Sabol
Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
Cody Ashby
Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR
Manish Adhikari
Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
Aric Anloague
Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
Japneet Kaur
Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
Sharmin Khan
Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR
Samrat Roy Choudhury
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, US; Pediatric Hematology-Oncology, Arkansas Children’s Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, 72202
Carolina Schinke
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, US; Myeloma Center; University of Arkansas for Medical Sciences, Little Rock, AR
Michela Palmieri
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases and Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR
C. Lowry Barnes
Department of Orthopedic Surgery; University of Arkansas for Medical Sciences, Little Rock, AR
Elena Ambrogini
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases and Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR
Intawat Nookaew
Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR
Jesus Delgado-Calle
Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, US; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR
Multiple myeloma (MM) remains incurable due to disease relapse and drug resistance. Notch signals from the tumor microenvironment (TME) confer chemoresistance, but the cellular and molecular mechanisms are not entirely understood. Using clinical and transcriptomic datasets, we found that NOTCH3 is upregulated in CD138+ cells from newly diagnosed MM (NDMM) patients compared to healthy individuals and increased in progression/relapsed MM (PRMM) patients. Further, NDMM patients with high NOTCH3 expression exhibited worse responses to Bortezomib (BOR)-based therapies. Cells of the TME, including osteocytes, upregulated NOTCH3 in MM cells and protected them from apoptosis induced by BOR. NOTCH3 activation (NOTCH3OE) in MM cells decreased BOR anti-MM efficacy and its ability to improve survival in in vivo myeloma models. Molecular analyses revealed that NDMM and PRMM patients with high NOTCH3 exhibit CXCL12 upregulation. TME cells upregulated CXCL12 and activated the CXCR4 pathway in MM cells in a NOTCH3-dependent manner. Moreover, genetic or pharmacologic inhibition of CXCL12 in NOTCH3OE MM cells restored sensitivity to BOR regimes in vitro and in human bones bearing NOTCH3OE MM tumors cultured ex vivo. Our clinical and preclinical data unravel a novel NOTCH3-CXCL12 pro-survival signaling axis in the TME and suggest that osteocytes transmit chemoresistance signals to MM cells.
