mTOR-driven metabolic shifts in cancers and in 3D bioprinted tissue-mimetic structures
Moldvai Dorottya
Pathological and Oncological Divison
Dr. Matolcsy András
Semmelweis Egyetem, I. sz Patológiai és Kísérleti Rákkutató Intézet tanterme
2025-12-04 14:30:00
Molekuláris és experimentális onkológia
Dr. Bödör Csaba
Dr. Sebestyén Anna
Nyitrayné Dr. Pap Erna
Dr. Gyukity-Sebestyén Edina
Dr. Fekete Andrea
Dr. Bugyik Edina
Dr. Koncz Gábor
Tumor metabolism is key in cancer development, and understanding its plasticity is
necessary for developing improved therapies. This study aimed to (1) develop and investigate
3D bioprinted preclinical cancer models and (2) examine mTOR activity and the tumorigenic
potential of tacrolimus (TAC) in post-transplant (post-tx) and de novo renal cell carcinoma
(RCC).
3D bioprinted cancer models were created using breast cancer and RCC cell lines, as
well as tumor-derived cells. 3D bioprinted tissue-mimetic structures (TMSs) were analyzed
through validated proliferation assays, histology, and molecular profiling. mTOR pathway
activity was examined in patients with end-stage renal disease (ESRD), post-tx and de novo
RCCs, while the effects of TAC were assessed in vitro and in vivo.
(1) The 3D bioprinted TMSs exhibited heterogenous expression of apoptosis and
proliferation markers, and showed reduced autophagy compared to 2D cultures, closely
mimicking in situ tumor characteristics. Enhanced membranous localization of β-catenin, Ecadherin,
and N-cadherin indicated improved cell–cell interactions, while nuclear translocation
of fibronectin and syndecan-1 suggested altered gene expression patterns in the 3D bioprinted
TMSs. Reduced sensitivity to mTOR inhibitors correlated with stress-mediated feedback and
lower baseline mTOR activity, as evidenced by decreased phospho-to-total ratios of mTORrelated
proteins and elevated pSAPK/JNK and TSC1 levels. Additionally, tumor-derived 3D
bioprinted TMSs more accurately replicated in situ drug responses compared to 2D monolayer
cultures and xenograft models.
(2) TAC treatment induced mTOR activation in situ, in vitro and in vivo, and promoted
growth in certain RCC cells. Notably, mTORC2 hyperactivation was more prevalent in post-tx
tumors compared to de novo RCCs and was also observed in ESRD kidneys, implicating
mTORC2 in both fibrosis and oncogenesis. Given mTORC2’s role in regulating cell survival,
metabolism, and metastasis, these findings underscore its importance in the pathology of posttx
malignancies.
In summary, 3D bioprinted cancer models provide a robust and physiologically relevant
platform for investigating tumor progression mechanisms and drug responses. In parallel, our
in situ tissue characterization and experimental data – further supported by in vitro and in vivo
findings – highlight the oncogenic potential of TAC-induced mTORC2 activation in RCC,
particularly in post-tx RCCs.
