The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming

Aidan R. Cole, Raquel Buj, Apoorva Uboveja, Nathaniel W. Snyder, Katherine M. Aird

1. 01

   Cisplatin-induced SASP enhanced detachment of high-grade serous ovarian cancer cells in vitro and dissemination in vivo

2. 02

   Fructose identified as a metabolic component of the SASP facilitating cell detachment

3. 03

   A high-fructose diet increased HGSOC dissemination in vivo

4. 04

   Complex I identified as the driver of SASP-mediated detachment and dissemination

5. 05

   Mechanism runs through SASP-mediated inhibition of an NAD-SIRT-SREBP axis, decreasing plasma-membrane cholesterol

6. 06

   Establishes the SASP as a metabolic phenotype that reprograms the tumour microenvironment in a paracrine fashion

Study Design

Preclinical Study

Sample Size

Not reported

Study Duration

Not applicable (preclinical models)

Methodology

Cisplatin-induced senescence models; conditioned-medium detachment assays; in vivo dissemination models of high-grade serous ovarian cancer; dietary fructose manipulation; metabolomics, complex I interrogation and NAD-SIRT-SREBP pathway analysis.

Limitations

Preclinical ovarian-cancer models only. This is not a general claim about dietary fructose and cancer risk in humans, and no human dietary or NAD-directed intervention has been tested against these endpoints. Relevance to NAD+ supplementation is mechanistic and hypothesis-generating: it indicates the NAD-SIRT-SREBP axis sits inside a pro-dissemination pathway in a chemotherapy context, which argues for caution rather than for any specific dosing change.