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

Projektinformationen

NIMICRY

ID Finanzhilfevereinbarung: 101045612

DOI

10.3030/101045612

Das Projekt endete am 21 März 2025

EK-Unterschriftsdatum 21 September 2022

Startdatum 1 Oktober 2022

Enddatum 30 September 2027

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 949 357,50

EU-Beitrag

€ 1 949 357,50

Koordiniert durch

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 1 - NIMICRY (Poor Prognosis Colorectal Cancers Display Self-sustained Growth by Niche-mimicry)

Berichtszeitraum: 2022-10-01 bis 2025-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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 investigated a radically different hypothesis: Mesenchymal CRCs display self-sustained growth by niche-mimicry (nimicry). I defined 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 employed state-of-the-art in vivo models, patient-derived organoids, and single cell sequencing combined with lineage tracing using advanced mathematical and bioinformatic analysis techniques, to address three main aims:
AIM 1: Unravel the signals that allow for niche-independent growth in a subset of colorectal cancers;
AIM 2: Determine the mode of growth of colorectal cancers characterized by niche-independence;
AIM 3: Establish the impact of niche-independence on tumour evolution and metastasis formation.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We could demonstrate that mesenchymal CRC cells have the ability for niche-independent proliferation by a multitude of autocrine loops, which supports the core hypothesis of the NIMCRY program. We found this property has major implications for the growth dynamics of mesenchymal cancers and contributes to the poor disease outcome of this subtype, including peritoneal dissemination. These results validated the central hypothesis of the NIMICRY program. We are currently finalizing a manuscript describing these findings.

Within this project, we have developed multiple bioinformatics tools to interrogate various types of RNA sequencing data for self-interactions or autocrine signalling. In a collaborative effort together with the bioinformatics team of Dr. Jan Koster, Amsterdam UMC, we were able to develop tools to calculate the number of different autocrine interaction pairs per cell from single cell sequencing data, using the annotated interaction database of CellPhoneDB. Similarly, we established methods to estimate the number of different autocrine interactions from bulk RNA sequencing, and implemented these data in the R2 Genomics Analysis and Visualization Platform (http://r2.amc.nl) where these metrics will be available for all researchers.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We could not execute the project to its full potential due to early termination of the project.