NIMICRY · Poor Prognosis Colorectal Cancers Display Self-sustained Growth by Niche-mimicry

Colorectal cancer (CRC) is a heterogeneous disease with widely variable clinical outcomes. I previously contributed to a unifying molecular classification of CRC, the consensus molecular subtypes (CMSs). The mesenchymal subtype (CMS4), representing ~25% of all CRC patients, is characterised by early metastatic dissemination and poor response to therapy. This is often attributed to activated and rich stroma and therefore much attention in the field goes to dissecting the interaction of the mesenchyme with the cancer cells in these tumours. However, in this research program I will investigate a radically different hypothesis: Mesenchymal CRCs display self-sustained growth by niche-mimicry (nimicry). I define nimicry as the adoption of niche features by cancer cells, thereby rendering the cancers independent of micro-environmental signals for their expansion. This hypothesis is directly based on preliminary experiments from my laboratory, which demonstrated that mesenchymal CRCs are not dependent on external growth factors for expansion in vitro and display autocrine and paracrine loops that drive self-sustained growth. The abundant stroma in mesenchymal CRCs is secondary to the growth factors and cytokines produced by the tumour cells.To study this concept, I will employ primary human CRC models in combination with molecular and functional characterisation, to delineate the self-supporting signalling loops in a patient specific fashion. These studies are paralleled by the investigation of clonal dynamics within established human CRCs by means of a novel genetic lineage tracing strategy in combination with quantitative analysis. Dedicated analyses will resolve the impact of nimicry on metastasis formation, therapy resistance and tumour evolution.These studies into nimicry as a critical concept in tumour biology, will importantly advance our understanding of the signals that drive CRC growth and progression, and will pave the way to new treatment strategies.