The Role of Perivascular Heterogeneity in Metastasis

Doruk Keskin ^1,3 Jiha Kim ^1,5 Vesselina G. Cooke ³ Chia-Chin Wu ² Hikaru Sugimoto ^1,3 Chenghua Gu ⁵ Michele De Palma ⁴ Raghu Kalluri ^1,3 Valerie LeBleu ^1,3

¹Cancer Biology, University of Texas MD Anderson Cancer Center, USA
²Genomic Medicine, University of Texas MD Anderson Cancer Center, USA
³Matrix Biology, Beth Israel Deaconess Medical Center and Harvard Medical School, USA
⁴Ecole Polytechnique Federale de Lausanne (EPFL), The Swiss Institute for Experimental Cancer Research (ISREC), Switzerland
⁵Neurobiology, Harvard Medical School, USA

Targeting tumor angiogenesis also inhibits the vessel-stabilizing properties of vascular pericytes. Pericyte targeting in early stages of tumor growth suppresses nascent angiogenesis and limits both tumor growth and metastatic dissemination. In contrast, pericyte targeting in tumors with pre-established vasculature resulted in enhanced intra-tumoral hypoxia, leading to cancer cell invasion and promoting metastasis. Our studies unraveled angiopoietin signaling as a key regulatory pathway associated with pericyte targeting and metastatic spread. Specifically, controlling Angiopoeitin-2 mediated signaling restored vascular stability associated with pericyte coverage loss in tumor angiogenesis, and suppressed tumor growth metastasis. These studies highlight the complexity and heterogeneity of pericytes in tumor angiogenesis and inform on novel combination therapy to control metastasis.