Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

The Growth of Neuroblastoma Cells in 2D or 3D Depends on the Expression of Cathepsin D: Implication for the Metastatic Process

Eleonora Secomandi
,
Andrea Esposito
ORCID logo ,
Giulia Camurani
,
Chiara Vidoni
,
Amreen Salwa
,
Letizia Vallino
ORCID logo ,
Alessandra Ferraresi
ORCID logo ,
Ciro Isidoro
* ORCID logo
Version 1 : Received: 25 January 2024 / Approved: 26 January 2024 / Online: 26 January 2024 (09:41:34 CET)

A peer-reviewed article of this Preprint also exists.

Secomandi, E.; Esposito, A.; Camurani, G.; Vidoni, C.; Salwa, A.; Lualdi, C.; Vallino, L.; Ferraresi, A.; Isidoro, C. Differential Competitive Growth of Transgenic Subclones of Neuroblastoma Cells Expressing Different Levels of Cathepsin D Co-Cultured in 2D and 3D in Response to EGF: Implications in Tumor Heterogeneity and Metastasis. Cancers 2024, 16, 1343. Secomandi, E.; Esposito, A.; Camurani, G.; Vidoni, C.; Salwa, A.; Lualdi, C.; Vallino, L.; Ferraresi, A.; Isidoro, C. Differential Competitive Growth of Transgenic Subclones of Neuroblastoma Cells Expressing Different Levels of Cathepsin D Co-Cultured in 2D and 3D in Response to EGF: Implications in Tumor Heterogeneity and Metastasis. Cancers 2024, 16, 1343.

Abstract

Neuroblastoma is an embryonal tumor arising from the sympathetic central nervous system. The epidermal growth factor (EGF) plays a role in neuroblastoma growth and metastatic behavior. Recently, we have demonstrated that cathepsin D (CD) contrasts EGF-induced neuroblastoma cell growth in 2D by downregulating EGFR/MAPK signaling. Aggressive NB is highly metastatic to the bone and the brain. In the metastatic process, adherent cells detach to form clusters of suspended cells that once reached the metastatic site adhere and form secondary colonies. Whether CD involves in survival of metastatic NB clones is not known. Therefore, in this study we addressed how CD differentially affects cell growth in suspension versus adherent condition. To mimic tumor heterogeneity, we co-cultured transgenic clones silenced for or overexpressing CD. We compared the growth kinetics of such mixed clones in 2D and 3D models in response to EGF, and we found that Over CD clone was advantaged for the growth in suspension, while the CD knocked-down clone was favored for the adherent growth as 2D. The fact that CD plays a dual role in cancer cell growth in 2D and 3D conditions indicates that during clonal evolution subclones expressing different level of CD may arise, which confers survival and growth advantages depending on the metastatic step. Whether CD involves in survival of metastatic NB clones is not known. We propose that epigenetic regulation of CD expression could be an additional strategy to prevent NB metastases.

Keywords

cancer; 3D neurospheres; lysosome; cell adhesion; clonal evolution; metastasis; tumor heterogeneity

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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