Network integration of thermal proteome profiling with multi-omics data decodes PARP inhibition

Complex disease phenotypes often span multiple molecular processes. Functional characterization of these processes can shed light on disease mechanisms and drug effects. Thermal Proteome Profiling (TPP) is a mass-spectrometry (MS) based technique assessing changes in thermal protein stability that can serve as proxies of functional protein changes. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomics and transcriptomics in a network-based approach using COSMOS, a multi-omics integration framework, to provide an integrated view of transcription factors, kinases and proteins with altered thermal stability. This allowed us to recover consequences of Poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer cells on cell cycle and DNA damage response as well as interferon and hippo signaling. We found that TPP offers a complementary perspective to other omics data modalities, and that its integration allowed us to obtain a more complete molecular overview of PARP inhibition. We anticipate that this strategy can be used to integrate functional proteomics with other omics to study molecular processes. Synopsis COSMOS, a network-based framework, can integrate functional proteomics data, such as Thermal Proteome Profiling (TPP), with other omics data modalities. It is used to generate multi-omics mechanistic hypotheses, as showcased in this study for PARP inhibition. Functional proteomics (TPP data) can be integrated with phosphoproteomics and transcriptomics in network models. TPP offers a complementary perspective to other omics data modalities. This approach provides a more complete and integrative overview of molecular processes related to PARP inhibition. COSMOS, a network-based framework, can integrate functional proteomics data, such as Thermal Proteome Profiling (TPP), with other omics data modalities. It is used to generate multi-omics mechanistic hypotheses, as showcased in this study for PARP inhibition.