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Abstract Mortality from cancer-associated sepsis varies by cancer site and host responses to sepsis are heterogenous. Native Hawaiians have the highest mortality risk from cancer-associated sepsis and colorectal cancer (CRC), even though they demonstrate lower CRC incidence compared to other ethnicities. We conducted a retrospective transcriptomic analysis of CRC tumors and adjacent non-tumor tissue from adult patients of Native Hawaiian and Japanese ethnicity who died from cancer-associated sepsis. We examined differential gene expression in relation to patient survival and sepsis disease etiology. Native Hawaiian CRC patients diagnosed with sepsis had a median survival of 5 (IQR 4–49) months, compared to 117 (IQR 30–146) months for Japanese patients. Transcriptomic analyses identified two distinct sepsis gene signatures classified as early response and late response sepsis genes that were significantly altered in the Native Hawaiian cohort. Analysis of canonical pathways revealed significant up and downregulation in mechanisms of viral exit from host cells (p = 4.52E−04) and epithelial junction remodeling (p = 4.01E−05). Key genes including elongation initiation factor pathway genes, GSK3B, and regulatory associated protein of mTOR (RPTOR) genes that protect cells from infection were significantly downregulated in Native Hawaiians. Genes promoting sepsis progression including CLOCK, PPBP and Rho family GTPASE 2 (RND2) were upregulated in Native Hawaiian patients. Our transcriptomic approach advances understanding of sepsis heterogeneity by revealing a role of genetic background and defining patient subgroups with altered early and late biological responses to sepsis. This study is the first to investigate differential gene expression in CRC-associated sepsis patients in relation to ethnicity. Our findings may lead to personalized approaches in stratifying patient mortality risk for sepsis and in the development of effective targeted therapies for sepsis.

Abstract Endosomal trafficking of cell surface receptors is essential to their function. Integrins are transmembrane receptors that integrate adhesion to the extracellular matrix with engagement of the cytoskeleton. Ligated integrins mediate diverse signals that regulate matrix assembly, cell survival, cell morphology, and cell motility. Endosomal trafficking of integrins modulates these signals and contributes to cell motility and is required for cancer cell invasion. The phosphoprotein PEA-15 modulates integrin activation and ERK MAP Kinase signaling. To elucidate novel PEA-15 functions we utilized an unbiased proteomics approach. We identified several binding partners for PEA-15 in the endosome including clathrin and AP-2 as well as integrin β1 and other focal adhesion complex proteins. We confirmed these interactions using proximity ligation analysis, immunofluorescence imaging, pull-down and co-immunoprecipitation. We further found that PEA-15 is enriched in endosomes and was required for efficient endosomal internalization of α5β1 integrin and cellular migration. Importantly, PEA-15 promotion of migration was dependent on PEA-15 phosphorylation at serines 104 and 116. These data support a novel endosomal role for PEA-15 in control of endosomal trafficking of integrins through an association with the β1 integrin and clathrin complexes, and thereby regulation of cell motility.