The roles of intratumour heterogeneity in the biology and treatment of pancreatic ductal adenocarcinoma

Abstract

Intratumour heterogeneity (ITH) has become an important focus of cancer research in recent years. ITH describes the cellular variation that enables tumour evolution, including tumour progression, metastasis and resistance to treatment. The selection and expansion of genetically distinct treatment-resistant cancer cell clones provides one explanation for treatment failure. However, tumour cell variation need not be genetically encoded. In pancreatic ductal adenocarcinoma (PDAC) in particular, the complex tumour microenvironment as well as crosstalk between tumour and stromal cells result in exceptionally variable tumour cell phenotypes that are also highly adaptable. In this review we discuss four different types of phenotypic heterogeneity within PDAC, from morphological to metabolic heterogeneity. We suggest that these different types of ITH are not independent, but, rather, can inform one another. Lastly, we highlight recent findings that suggest how therapeutic efforts may halt PDAC progression by constraining cellular heterogeneity.

Fig. 1. Only a subset of PDAC cells—the CSCs—have tumour-initiating capacity.

CSCs are marked by a variety of cell surface markers and/or transcriptional programs.

Fig. 2. Both classical and squamous-like PDAC cells—defined by different transcriptional and epigenetic programs—can be found within a single tumour.

Patients whose PDACs exhibit predominantly classical features have a better prognosis than those whose tumours exhibit predominantly squamous features, such as higher KRAS activity and mutations in epigenetic modifiers.

Fig. 3. PDAC cells along the EMT spectrum express different markers and exhibit different behaviours.

In particular, recent work highlights the existence of hybrid or partial EMT states that combine features of epithelial and mesenchymal tumour cells.

Fig. 4. PDAC tumours contain spatially distinct metabolic zones.

Metabolic heterogeneity and associated differences in metabolic pathways within tumours (e.g. lactate production vs. uptake) affect tumour cell phenotypes and therapeutic responses.