"Preventing treatment-related toxicities is an urgent issue in (paediatric) cancer care. Previous research has demonstrated that short-term fasting temporarily supresses cellular growth pathways while upregulating protective defence and resilience mechanisms, thereby increasing the resistance of healthy cells to damage. Here, we investigated whether fasting preconditioning could prevent damage to healthy cells caused by chemotherapeutic agents used in cancer treatments.

We subjected young WT mice to short-term fasting and monitored outcomes related to toxicity. Furthermore, we used a fasting-mimicking medium, containing reduced levels of glucose and growth factors, to model fasting in vitro.

Cisplatin treatment expectedly resulted in reduced food intake and body weight loss in mice, which was partially reversed by fasting preconditioning. More strikingly, fasting significantly increased survival: whereas all control mice died within 6 days of treatment, 50% of the fasted mice were alive 160 days later. In vitro investigations further revealed that altering the timing of the fasting to encompass not only the period before, but also during treatment, resulted in improved protection from cisplatin-, doxorubicin- and irinotecan-induced cell death.

Overall, this study pointed to positive effects of fasting on resilience to chemotherapy toxicity and survival, with indications of the timing of the intervention being of importance. "

Giulia Perticari*, Jeff De Martino*, Arianna Fumagalli*, Jolanda Kooiman, Sofia Doulkeridou, Jarno Drost.

"Malignant rhabdoid tumours (MRTs) are highly aggressive childhood cancers characterised by rapid progression, early metastasis, and poor prognosis. Despite this aggressiveness, MRTs are genetically simple, driven almost exclusively by inactivating mutations in SMARCB1, a core component of the SWI/SNF chromatin-remodelling complex. This genetic stability suggests that tumour evolution is largely governed by epigenetic and transcriptional heterogeneity arising from aberrant chromatin regulation.
Here, we provide the first systematic analysis of clonal and transcriptional evolution in MRTs in vitro and in vivo using high-complexity barcode lineage tracing in patient-derived MRT organoid models. Barcoded organoids were orthotopically transplanted into mice and, in parallel, maintained in vitro. Primary tumours, matched metastases, and in vitro organoids were subsequently analysed by single-cell profiling.
We observed a pronounced reduction in clonal complexity in vivo compared with in vitro cultures, despite a stable genetic background. While many clones engrafted, only a small subset contributed to primary tumour growth, and even fewer gave rise to largely monoclonal metastases. Notably, (pro)metastatic clones displayed distinct transcriptional programs linked to metabolic rewiring and extracellular matrix remodelling. Overall, our integrated approach uncovers striking clonal dynamics in MRTs and highlights non-genetic mechanisms driving tumour growth and metastasis."