Intrinsic metastatic resistance versus origin or post-dissemination evolution

Determine whether metastatic tumours are intrinsically more resistant to chemotherapeutic agents than their corresponding primary tumours, or whether the reduced therapeutic sensitivity observed in metastatic lesions results from selection of particularly aggressive, drug-tolerant subpopulations at the primary site or from evolutionary changes acquired after dissemination to secondary sites.

Background

Metastases account for the vast majority of cancer-related mortality, and numerous studies report that standard chemotherapy often controls primary tumours but fails to impact metastatic populations. There is also substantial evidence of a strong correlation between treatment resistance and metastatic ability, with more drug-tolerant cancer cells frequently exhibiting enhanced dissemination.

Despite these observations, the causal basis for the apparent increased resistance of metastases remains unresolved. It is unclear whether metastatic lesions possess an intrinsic resistance phenotype independent of their origin, or whether their reduced sensitivity is a consequence of selection for aggressive subclones in the primary tumour and/or further evolution after colonizing distant tissues. The paper proposes a mathematical framework to explore these hypotheses but highlights the underlying biological question as open.