Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance

期刊论文
出版模式：

开放获取
发表日期：

2024年6月14日

查看全文

Vitale Del Vecchio,
Ayesha Rehman,
Sameer Kumar Panda,
Martina Torsiello,
Martina Marigliano,
Maria Maddalena Nicoletti,
Giuseppe Andrea Ferraro,
Vincenzo De Falco,
Rosamaria Lappano,
Eva Lieto,
Francesca Pagliuca,
Carlo Caputo,
Marcella La Noce,
Gianpaolo Papaccio,
Virginia Tirino,
Nirmal Robinson,
Vincenzo Desiderio,
Federica Papaccio

摘要

Background

Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes.

Methods

We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis.

Results

We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring.

Conclusions

We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.