Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Pancreatic stellate cells (PSCs) differentiate into cancer-associated myofibroblasts, driving pancreatic ductal adenocarcinoma (PDAC) progression.
• Tumor microenvironment interactions, particularly between cancer cells and PSCs, are critical for PDAC development.

Purpose of the Study:

• To investigate cooperative mechanisms between cancer and stellate cells in a 3D context.
• To identify specific molecular players involved in cancer-stellate cell crosstalk and myofibroblast differentiation.

Main Methods:

• Generation of chimeric spheroids using human and mouse cancer and stellate cells.
• Species-specific deconvolution of bulk RNA sequencing data to analyze cell type-specific transcriptomes.
• Functional and proteomic analyses to elucidate enzyme mechanisms.

Main Results:

• Stellate cell-specific expression of collagen-processing enzymes ADAMTS2 and ADAMTS14 was identified.
• Loss of ADAMTS2 reduced myofibroblast differentiation and invasion, while loss of ADAMTS14 promoted them.
• ADAMTS2 and ADAMTS14 exhibit opposing roles in regulating transforming growth factor beta availability via distinct substrates (Serpin E2 and fibulin 2, respectively).

Conclusions:

• ADAMTS2 and ADAMTS14 play novel, opposing roles in regulating pancreatic cancer stroma and myofibroblast differentiation.
• These enzymes represent a new regulatory axis influencing PDAC malignant behavior.
• Understanding these interactions provides insights into therapeutic strategies targeting the tumor microenvironment.