A systematic study of paralog and protein complex response to gene loss in cancer

Proteins operate as part of intricate interaction networks within the cell, frequently forming dimers and larger protein complexes. Despite suffering frequent genetic alterations that perturb these networks, cancer cells continue to grow and thrive. In this thesis, we leverage proteomic profiles of tumours and cell lines to understand how the protein-protein interaction networks within tumour cells respond to genetic perturbations, particularly gene deletions. Paralogs, duplicate genes, can confer robustness to gene loss through functional redundancy. However, the mechanistic basis of paralog compensation is not well understood. In the first results chapter, we study how paralog abundances vary in response to gene loss by analyzing proteomic profiles of paralog knockouts in isogenic cell lines and instances of hemizygous gene loss in the CPTAC PanCan tumour proteomic dataset. We identify hundreds of cases where gene loss correlates with either increased paralog abundance (compensation) or decreased paralog abundance (collateral loss). Compensation pairs are more sequence-similar, belong to smaller families, and tend to share protein-protein interaction partners. Compensation pairs are also more essential and are highly enriched among known synthetic lethal pairs. Many of these regulatory relationships act only at the protein level, potentially mediated through decreased degradation of the compensating protein. In the second results chapter, we show that proteomic co-abundance from CCLE and CPTAC outperform DepMap gene essentiality correlations for predicting protein complexes, with cell lines and tumour proteomes generally predicting similar complexes. We then integrate interactomic evidence with proteomic co-abundance to identify a set of pan-cancer protein complexes with context-dependent expression patterns. In 29 cases, complexes show decreased abundance upon the deletion or mutation of a subunit, with this effect rarely being detectable at the protein level. This suggests post-transcriptional regulation plays a major role in cancer-associated network rewiring, adding to earlier findings regarding protein complex collateral loss in cancer. Overall, our results illustrate how protein-protein interaction networks in cancer cells rewire in response to gene loss, revealing both compensatory mechanisms and potentially targetable vulnerabilities.