USP7 inhibitors suppress tumour neoangiogenesis and promote synergy with immune checkpoint inhibitors by downregulating fibroblast VEGF.

Background: Understanding how to modulate the microenvironment of tumors that are resistant to immune checkpoint inhibitors represents a major challenge in oncology.Here we investigate the ability of USP7 inhibitors to reprogram the tumor microenvironment (TME) by inhibiting secretion of vascular endothelial growth factor (VEGF) from fibroblasts.

Methods: To understand the role played by USP7 in the TME, we systematically evaluated the effects of potent, selective USP7 inhibitors on co-cultures comprising components of the TME, using human primary cells.

Cancer-Associated Fibroblasts Produce Netrin-1 to Control Cancer Cell Plasticity.

Netrin-1 is upregulated in a large fraction of human neoplasms. In multiple animal models, interference with netrin-1 is associated with inhibition of tumor growth and metastasis. Although netrin-1 upregulation was initially described in cancer cells, we report here that in the human colorectal cancer database, the expression of netrin-1 and its receptor UNC5B correlates with a cancer-associated fibroblasts (CAF) signature.

Identification and characterisation of STMN4 and ROBO2 gene involvement in neuroblastoma cell differentiation.

To better understand neuroblastoma differentiation, we used microarray analysis to identify common gene expression changes from three differentiation models. This revealed STMN4 and ROBO2 to be consistently up-regulated in differentiated neuroblastoma cells induced by chromosome 1 transfer, MYCN knockdown, and 9-cis retinoic acid (9cRA). Furthermore, stable expression of transfected STMN4 or ROBO2 induced differentiation in IMR-32 cells.