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Defining heterocellular signalling within the intratumoral stem cell niche of colorectal cancer

Periodic Reporting for period 2 - IntratumoralNiche (Defining heterocellular signalling within the intratumoral stem cell niche of colorectal cancer)

Periodo di rendicontazione: 2020-07-01 al 2021-12-31

Purpose:
Cells in a tumor are highly heterogeneous. The role and consequence of having multiple cell types
within a cancer is mostly centered towards the function of cancer stem cells (CSCs) since they are the driving
forces of tumor growth. However, even the most malignant cancers contain differentiated tumor cells. Is there a functional role for these cells,
for instance by providing signaling cues that support CSC function. In other words, do colorectal tumors build their own stem cell supporting niche?

Importance for society:
My overarching aim is to identify and characterize the cell-cell signaling pathways between cancer stem cells and differentiated tumor cells (intratumoral stem cell niche) that are vital for colorectal tumor growth and metastasis formation.

Objectives:
-Identify cell-cell signaling pathways that act between cancer stem cells and differentiated tumor cells
-Develop new technological strategies to characterize signaling activities in real-time and with single-cell resolution in 3-dimensional tumor organoids of patients
-Functional investigation of candidate genes that are essential components of the intratumoral stem cell niche
We are mapping and characterizing the signaling pathways during outgrowth experiments of patients-tumor organoids. These are a proxy for clonal liver metastases formation from primary colon cancer.

We established real-time quantification of EGFR/MAPK signaling activity in single tumor cells of patient organoids. This enables us to study drug response in real-time, as well as revealed that the EGFR receptor is a strong amplifier of downstream signaling activity, even when this pathway contains frequent cancer mutations in KRAS or BRAF.

To facilitate functional studies on many genes in patient organoids, we developed new CRISPR strategies for efficient knock-ins (e.g. fluorescent gene tags) and (conditional) knock-outs.
Developed strategies that provide insights into real-time signaling activity in tumor organoids and its quantitative assessment upon targeted therapies is a technological breakthrough. We aim to expand our toolbox to study more signaling pathways.
patient organoids