Clinical implications of intratumor heterogeneity: challenges and opportunities

Abstract

In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Functionally, heterogeneity provides tumors with significant adaptability. This ranges from mutual beneficial cooperation between cells, which nurture features such as growth and metastasis, to the narrow escape and survival of clonal cell populations that have adapted to thrive under specific conditions such as hypoxia or chemotherapy. These dynamic intercellular interplays are guided by a Darwinian selection landscape between clonal tumor cell populations and the tumor microenvironment. Understanding the involved drivers and functional consequences of such tumor heterogeneity is challenging but also promises to provide novel insight needed to confront the problem of therapeutic resistance in tumors.

Keywords: Antitumor therapeutics; Artificial intelligence; Intratumor heterogeneity; Liquid biopsy.

Fig. 1

Lung cancer intratumoral heterogeneity at morphological and molecular levels. a Paraffin section of a lung tumor biopsy showing three main morphological subtypes within the same tumor. b Molecular and biomarker analysis confirming heterogeneity in EGFR mutation and in the c transcriptional signature of these three subtypes

Fig. 2

Clonal cooperation and cellular consortium. a Darwinian model of clonal heterogeneity resulting in a consortium of clones, each with their characteristics and malignant features. b Cooperation between several clones to invade and metastasize

Fig. 3

Cancer biology-driven personalized medicine. Schematic representation of the clinical workflow for lung cancer diagnosis, treatment, and follow-up