Paracrine signalling between intestinal epithelial and tumour cells induces a regenerative programme

Area of Science:

• Oncology
• Cell Biology
• Developmental Biology

Background:

• Tumors are complex ecosystems where cancer cells interact with surrounding tissues.
• The influence of cancer cells on healthy neighboring cells is not fully understood.
• Stromal cells' role in tumor growth is known, but cancer cell impact on normal tissue is less defined.

Purpose of the Study:

• To investigate the impact of mutant cancer cells on neighboring healthy tissues.
• To uncover the mechanisms by which cancer cells influence non-cancerous cells.
• To identify factors mediating intercellular communication in intestinal tumors.

Main Methods:

• Utilized mouse intestinal organoids as a model system.
• Investigated paracrine signaling pathways between cancer and healthy epithelial cells.
• Employed transcriptomic and morphological analyses to study cellular responses.

Main Results:

• Discovered that intestinal cancer cells reactivate fetal and regenerative YAP-associated transcriptional programs in neighboring wildtype epithelial cells.
• Identified thrombospondin-1 (THBS1) as the key mediator of these non-cell-autonomous responses.
• Demonstrated that THBS1 facilitates adaptation of normal cells to the tumor microenvironment.

Conclusions:

• The THBS1-YAP axis is a critical paracrine mechanism in intestinal tumors.
• Cancer cells induce adaptive changes in neighboring healthy cells via THBS1 and YAP.
• THBS1 is a potential prognostic marker and therapeutic target in human cancers.