Abstract

Pancreatic ductal adenocarcinoma is characterised by an extensive desmoplastic reaction, which on average constitutes ~85% of the tumour volume. Tumour cells coerce host cells, such as fibroblasts and myeloid cells, to remodel the stroma, which results in altered stiffness, cell-cell signalling and modified tumour cell function. The rules governing tumour-stromal interactions are currently not clearly defined. We recently described an oncogene-driven signalling axis, whereby cancer cells co-opt stromal cells to elicit reciprocal signals and engage additional signalling pathways in the cancer cells (Tape et al Cell 2016). To further our understanding of tumour-stroma interactions, and to better understand the impact of tumour cell diversity, we have established a model of intra-tumoral heterogeneity in PDA. Intriguingly, individual clonal populations differentially interact with co-cultured pancreatic fibroblasts to direct the activation of specific transcriptional programmes and distinct reciprocal signals. Conversely, tumour cell clones display differential sensitivity to reciprocal signals and engage distinct signalling pathways. This suggests that clonal tumour cell populations differentially engage nearby stromal cell populations to drive a specific phenotype, which may further complicate selection of targeted therapies.