Zhong, J.;Dannenfelser, R.;Yao, V.

Alternative splicing generates extensive transcript diversity in cancer, but whether the resulting changes to protein-protein interaction (PPI) networks are structured across tumors or idiosyncratic to individual patients remains unresolved. Existing analyses catalog splicing events and their effects on individual interactions, but do not reconstruct patient-specific interaction networks at scale, leaving the systems-level architecture of splicing-driven rewiring uncharacterized. Here, focusing on exon skipping, the most prevalent form of alternative splicing in humans, we analyze 7,950 tumors across 28 cancer types to reconstruct patient-specific rewired PPI networks relative to matched normal tissues, distinguishing interaction gains from losses. We identify widespread and structured remodeling of protein connectivity, including a unique pattern of interaction gains in brain cancers, a conserved pan-cancer axis of interaction loss that converges on GTPase and Ras signaling, and a subset of genes that function as bidirectional switches, where rewiring direction varies across cancer types. At the patient level, tumors exhibiting extreme rewiring, especially pronounced interaction gains, are associated with significantly poorer survival, independent of tumor stage and mutational burden. These results delineate systems-level patterns through which alternative splicing reshapes protein interaction networks and contributes to tumor heterogeneity across cancers.