Abstract
Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor growth has demonstrated limited activity in the clinical setting. New molecular understanding of integrins have revealed that these receptors can regulate both pro‑ and anti‑tumorigenic functions in a cell type‑dependent manner. Therefore, designing strategies that block pro‑tumorigenic signaling, without impeding anti‑tumorigenic functions, may lead to development of more effective therapies. In the present study, evidence was provided for a novel signaling cascade in which β3‑integrin‑mediated binding to a secreted RGDKGE‑containing collagen fragment stimulates an autocrine‑like signaling pathway that differentially governs the activity of both YAP and (protein kinase‑A) PKA, ultimately leading to alterations in the levels of immune checkpoint molecule PD‑L1 by a proteasome dependent mechanism. Selectively targeting this collagen fragment, reduced nuclear YAP levels, and enhanced PKA and proteasome activity, while also exhibiting significant antitumor activity in vivo. The present findings not only provided new mechanistic insight into a previously unknown autocrine‑like signaling pathway that may provide tumor cells with the ability to regulate PD‑L1, but our findings may also help in the development of more effective strategies to control pro‑tumorigenic β3‑integrin signaling without disrupting its tumor suppressive functions in other cellular compartments.