Sissi Dolci, Loris Mannino, Eros Rossi, Emanuela Bottani, Francesca Ciarpella, Nicola Piazza, Isabel Karkossa, Marzia Di Chio, Benedetta Savino, B Lucidi, G. Pruonto, Ilaria Barone, Alessandra Campanelli, Francesca Cersosimo, Elisa Setten, Stefano Gianoli, Z. Malik, Giuseppe Busetto, Alex Pezzotta, Alessandra Castagna, Nicolò Martinelli, Silvia Ferretti, Federico Boschi, Adam Doherty, Maria Teresa Scupoli, Chiara Cavallini, Giorgio Malpeli, Alessia Amenta, Ludovica Sagripanti, Vincenzo Silani, Patrizia Cristofori, Eugenio Scanziani, Marco Sandri, Anna Pistocchi, Patrizia Bossolasco, Marco Endrizzi, Kristin Schubert, Guido Francesco Fumagalli, M. Locati, Francesco Bifari, I. Decimo
Tumor-associated macrophages (TAMs) enhance cancer progression by promoting angiogenesis, extracellular matrix remodeling, and immune suppression. Nerve infiltration also contributes to tumor growth. However, the role of TAMs in promoting intratumoral nerve growth remains unclear. In this study, we have shown that TAMs express a distinct neural growth gene signature. TAMs actively enhanced neural growth within tumors and directly promoted in vitro neurite outgrowth. We identified secreted phosphoprotein 1 (SPP1) as a required mediator of TAM-driven neural growth and mTORC2 activation. Leveraging this TAM-neural growth function, we explored TAM neuroregenerative potential. Adoptive transfer of TAMs in severe complete-compressive-contusive spinal cord injury (scSCI) increased neuronal survival, axonal regrowth, and motor function recovery. Moreover, TAMs healed scSCI microenvironment and remodeled the cyst. Functional and proteomic analyses confirmed SPP1 and neural Rictor as necessary molecular mediators for TAM-induced regeneration. Our data unveil a role for TAMs in tumor innervation and neural tissue repair.