The growth and spread of malignant tumors such as ovarian carcinomas are governed in part by complex interconnected-signaling cascades occurring between stromal and tumor cells. These reciprocal cross-talk signaling networks operating within the local tissue microenvironment may enhance malignant tumor progression. Understanding how novel bioactive molecules generated within the tumor microenvironment regulate signaling pathways in distinct cellular compartments is critical for the development of more effective treatment paradigms. Here, we provide evidence that blocking cellular interactions with an RGDKGE-containing collagen peptide that selectively binds integrin β3 on ovarian tumor cells, enhances the phosphorylation of the hippo effector kinase LATS1, and reduces nuclear accumulation of YAP and its target gene c-Myc. Selectively targeting this RGDKGE-containing collagen fragment inhibited ovarian tumor growth and the development of ascites fluid in vivo. These findings suggest that this bioactive collagen fragment may represent a previously unknown regulator of the hippo effector kinase LATS1 and regulates ovarian tumor growth by a YAP dependent mechanism. Taken together, these data not only provide new mechanistic insight into how a unique collagen fragment may regulate ovarian cancer, but in addition may help provide a potentially useful new alternative strategy to control ovarian tumor progression based on selectively disrupting a previously unappreciated signaling cascade.Copyright © 2020. Published by Elsevier Inc.