Biology subjects

Harnoss, J. M.

Publications and source records attributed to Harnoss, J. M..

4 recordsLinked to original sources

bioRxiv2026

Preoperative biliary stenting is associated with functional dysbiosis and impaired bile acid metabolism in pancreatic cancer - Impact of preoperative biliary stenting on gut microbiota

Recent evidence suggests that the gut microbiome plays a role in the development and treatment response of pancreatic ductal adenocarcinoma (PDAC). However, the functional impact of tumor location and preoperative biliary stenting (PBS) on microbial composition and metabolism remains poorly understood. In this prospective study, preoperative stool specimens were collected from patients undergoing surgery for PDAC at Heidelberg University Hospital, Germany, between March 2020 and July 2021. Whole-genome shotgun metagenomic sequencing was performed to characterize microbial composition and functional pathways. A total of 63 preoperative stool samples were analyzed, including 40 patients with pancreatic head tumors (63.5%) and 23 with body/tail tumors (36.5%). Microbial community composition differed significantly according to tumor location (Bray-Curtis, p=0.005), with enrichment of Ruminococcus bromii in body/tail tumors. Among patients with pancreatic head tumors, PBS was associated with reduced alpha diversity (Shannon index, p=0.04), depletion of taxa including members of the Eubacteriales and Clostridiales orders as well as the genera Raoultella and Prevotella, and reduced abundance of selected genes involved in secondary bile acid metabolism. PBS was also associated with a higher rate of major postoperative complications according to Clavien-Dindo >3a (28.6% vs 3.8%; p=0.04). These findings suggest that biliary intervention may induce functional dysbiosis characterized by reduced microbial diversity and impaired bile acid metabolism, potentially disrupting host- microbiome crosstalk and contributing to adverse postoperative outcomes in pancreatic cancer.

microbiology↗

bioRxiv2021

Antigen-derived peptides directly engage the unfolded-protein sensor IRE1α to curb cross-presentation by dendritic cells

Dendritic cells (DCs) promote adaptive immunity by cross-presenting antigen-based epitopes to CD8+ T cells. DCs process internalized protein antigens into peptides that enter the endoplasmic reticulum (ER) and upload onto major histocompatibility type I (MHC-I) protein complexes for cell-surface transport and cross-presentation. Perplexingly, DCs often exhibit activation of the ER-stress sensor IRE1 in the absence of classical ER stress--leaving the underlying mechanism unexplained. Here we show that antigen-derived hydrophobic peptides directly engage ER-resident IRE1 by masquerading as unfolded proteins. Furthermore, IRE1 activation depletes MHC-I heavy-chain mRNAs through regulated IRE1-dependent decay (RIDD), thereby curtailing antigen cross-presentation. In tumor-bearing mice, IRE1 disruption increased MHC-I expression on tumor-infiltrating DCs, and enhanced recruitment and activation of CD8+ T cells. Moreover, IRE1 inhibition synergized with anti-PD-L1 antibody treatment to cause tumor regression. Our findings elucidate the mechanism and consequence of antigen-driven IRE1 activation in DCs, yielding a promising combination strategy for cancer immunotherapy.

cell biology↗

bioRxiv2021

Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival

Eukaryotic IRE1 mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, mammalian RIDD seemingly targets only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1-controlled mRNAs in human breast cancer cells, we discovered not only canonical endomotif-containing RIDD substrates, but also many targets lacking recognizable motifs--degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1 displayed two basic endoribonuclease modalities: endomotif-specific cleavage, minimally requiring dimers; and endomotif-independent promiscuous processing, requiring phospho-oligomers. An oligomer-deficient mutant that did not support RIDDLE failed to rescue cancer-cell viability. These results link IRE1 oligomers, RIDDLE, and cell survival, advancing mechanistic understanding of the UPR.

cancer biology↗

bioRxiv2018

Disruption of IRE1α through its Kinase Domain Attenuates Multiple Myeloma

Multiple myeloma (MM) arises from malignant immunoglobulin-secreting plasma cells and remains an incurable, often lethal disease despite recent therapeutic advances. The unfolded-protein response sensor IRE1 supports protein secretion by deploying a kinase-endoribonuclease module to activate the transcription factor XBP1s. MM cells may coopt the IRE1-XBP1s pathway; however, the validity of IRE1 as a potential MM therapeutic target is controversial. Here we show that genetic disruption of IRE1 or XBP1s, or pharmacologic IRE1 kinase inhibition, attenuated subcutaneous or orthometastatic growth of MM tumors in mice, and augmented efficacy of two well-established frontline antimyeloma agents, bortezomib or lenalidomide. Mechanistically, IRE1 perturbation inhibited expression of key components of the ER-associated degradation machinery, as well as cytokines and chemokines known to promote MM growth. Selective IRE1 kinase inhibition reduced viability of CD138+ plasma cells while sparing CD138- cells from bone marrow of newly diagnosed MM patients or patients whose disease relapsed after 1 - 4 lines of treatment in both US- and EU-based cohorts. IRE1 inhibition preserved survival and glucose-induced insulin secretion by pancreatic microislets. Together, these results establish a strong therapeutic rationale for targeting IRE1 with kinase-based small-molecule inhibitors in MM.\n\nSignificance statementMultiple myeloma (MM) is a lethal malignancy of plasma cells. MM cells have an expanded endoplasmic reticulum (ER) that is constantly under stress due to immunoglobulin hyperproduction. The ER-resident sensor IRE1 mitigates ER stress by expanding the ERs protein-folding capacity while supporting proteasomal degradation of misfolded ER proteins. IRE1 elaborates these functions by deploying its cytoplasmic kinase-RNase module to activate the transcription factor XBP1s. The validity of IRE1 as a potential therapeutic target in MM has been questioned. Using genetic and pharmacologic disruption in vitro and in vivo, we demonstrate that the IRE1-XBP1s pathway plays a critical role in MM growth. We further show that IRE1s kinase domain is an effective and safe potential small-molecule target for MM therapy.

cancer biology↗