Biology subjects

Fichtner-Feigl, S.

Publications and source records attributed to Fichtner-Feigl, S..

6 recordsLinked to original sources

bioRxiv2026

Immunomodulatory impact of PTPN11/SHP2-based vertical RAS-MAPK pathway inhibition in pancreatic cancer

Protein tyrosine phosphatase non-receptor 11 (PTPN11/SHP2) is a critical upstream mediator of RAS-MAPK signaling and a central node in adaptive resistance mechanisms evolving with RAS and MEK/ERK inhibition. Accordingly, clinical trials are currently evaluating allosteric SHP2 inhibitors in vertical RAS pathway combination therapies for various KRAS-mutant malignancies, including pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to delineate the immunomodulatory effects of SHP2-based vertical RAS pathway inhibition in notoriously immunotherapy-refractory PDAC, spanning from early treatment response to invariably evolving adaptive resistance. Employing human and murine PTPN11 knockout and wild-type PDAC cell lines, an autochthonous murine PDAC model (KPC), and patient-derived PDAC organoids, we find that short term dual MEK/SHP2 inhibition induces increased T cell infiltration and a reduction in immunosuppressive M2-like macrophages. However, these effects are accompanied by a decrease in mature dendritic cells and a concomitant expansion of monocytic myeloid-derived suppressor cells, indicative of a mixed immunological response with both immune-activating and immune-suppressing features. These changes are associated with tumor cell-intrinsic upregulation of CXCR3 ligands and TGF-{beta}, as well as increased expression of checkpoint ligands for TIGIT and TIM-3 across molecular subtypes and species. With prolonged treatment and transition to an adaptive resistant tumor cell state, the initial immune-sensitizing effects are lost and the immune-suppressive features prevail. M2-like macrophages re-accumulate, dendritic cell maturation remains impaired, TGF-{beta} expression persists, and TIGIT and TIM-3 ligand expression is further enhanced. Notably, dual SHP2/RAS inhibition recapitulates the observed induction of TGF-{beta} and checkpoint ligands. Collectively, these findings identify a dynamic but ultimately immunosuppressive remodeling of the tumor microenvironment in response to SHP2-based vertical RAS pathway inhibition in PDAC and provide a rationale for combinatorial immunotherapy strategies. In particular, concurrent targeting of TGF-{beta}, combined TIGIT/TIM-3 checkpoint blockade, and likely CD40 agonism may help sustain early immune activation while counteracting emerging suppressive features, thereby improving the durability of tumor control.

immunology↗

bioRxiv2026

Membrane localisation and checkpoint blockade enhance xenoantigen delivery to redirect pre-existing immunity against tumours

Cancer immunotherapies often rely on the recognition of tumour antigens, which strongly limits their efficacy upon heterogeneous antigen expression or downregulation. A strategy to overcome this limitation is to redirect pre-existing antiviral immunity against tumours through the delivery of xenoantigens. While many studies have addressed this by repurposing licensed vaccines, we here investigated the underlying mechanisms of immune redirection via the delivery of non-adjuvanted xenoantigen proteins, thereby avoiding confounding adjuvant- or pathogen-specific effects. Using B16F10 melanoma cells engineered to express the model antigen OVA, we found that tumour rejection in pre-immunised mice depends on the subcellular localisation of the xenoantigen, with membrane-bound antigens eliciting stronger rejection than dose-matched soluble cytoplasmic antigens. Enhanced rejection of membrane-bound OVA expressing tumours was associated with stronger CD4+ T cell responses. In addition, pre-immunisation also increased recruitment of inflammatory monocytes and macrophages at the tumour site. To translate this concept therapeutically, we developed a membrane-targeting OVA fusion protein which, upon intratumoural delivery, redirected pre-existing immunity and made tumours responsive to anti-PD-1 therapy. Importantly, these findings were further validated using the clinically relevant varicella zoster virus (VZV) glycoprotein E (gE) antigen and the licensed varicella vaccine Varivax. Our approach provides a mechanistic and translational perspective for treating poorly immunogenic tumours, leveraging widespread pathogen-specific immune memory in combination with anti-PD1 therapy in cancer patients.

cancer biology↗

bioRxiv2026

Lipotoxic fingerprints in clinically relevant postoperative pancreatic fistula: fatty acid driven cytotoxicity targets cells involved in anastomotic healing

Background & AimsClinically relevant postoperative pancreatic fistula (CR-POPF) remains a major cause of morbidity following pancreatic surgery, potentially due to fatty acid release by lipase activity. This study investigated how the biochemical composition of CR-POPF effluents drives cellular injury and transcriptional stress responses. MethodsDrain effluents from 14 patients undergoing pancreatoduodenectomy (7 with CR-POPF and 7 controls) were analyzed using gas chromatography-mass spectrometry. Candidate lipids were tested on human foreskin fibroblasts, mesothelial cells, and pancreatic epithelial cells using viability and cytotoxicity assays. Effluents were applied directly to cultures, and RNA sequencing was performed on cells exposed to the two most cytotoxic CR-POPF samples. ResultsMetabolomic profiling revealed lipolytic traits characterized by long-chain saturated fatty acids, including palmitic and stearic acid, and the palmitic acid monoacylglycerol monopalmitin, in drain effluents. These fatty acids accounted for over 70% of the variance in multivariate metabolomic analyses between CR-POPF and control groups. Dose-response assays confirmed concentration-dependent cytotoxicity (p < 0.0001), with a subtoxic threshold of 0.2 mM. Two effluents (AES1448 and GR1479) consistently reduced cell viability across models (F > 19, p < 0.0001). Transcriptomic profiling showed enrichment of inflammatory, unfolded-protein, and stress-response pathways, along with suppression of proliferation modules. GR1479 induced metabolic adaptation, whereas AES1448 and monopalmitin triggered overt lipotoxic stress. ConclusionsLipolysis-derived lipids may mediate stromal and mesothelial injury in CR-POPF. Integrating metabolomic, functional, and transcriptomic data uncovers a spectrum of cellular responses, spanning from adaptive remodeling to lipolysis-driven proteotoxic stress. These findings support lipid toxicity as a biochemical property of CR-POPF and a potential target for prevention. SynopsisThis study identifies long-chain saturated fatty acids in postoperative pancreatic effluents as key mediators of cytotoxic and inflammatory stress. Integrating metabolomic and transcriptomic analyses link effluent composition directly to cellular injury and impaired healing after pancreatic surgery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/705517v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@2ba175org.highwire.dtl.DTLVardef@752522org.highwire.dtl.DTLVardef@d8f823org.highwire.dtl.DTLVardef@8acb7f_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

cell biology↗

bioRxiv2025

Vertical RAS-pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations

Background & AimsOncogenic KRAS mutations drive metabolic rewiring in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to an invariably evolving resistance. MethodsTo understand the metabolic changes induced by dual inhibition, we comprehensively tested cell lines, endogenous tumor models, and patient-derived organoids representing the full spectrum of PDAC molecular subtypes. ResultsWe find that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major mitochondrial alterations, elevates reactive oxygen species (ROS) levels and triggers a lipid peroxidase dependency. While anabolic pathways, glycolysis and autophagy were also affected, mitochondrial alterations persisted longterm into a therapy resistant state. ConclusionsThe resulting vulnerability to induction of ferroptotic cell death via combined SHP2/MEK1/2 and glutathione peroxidase (GPX4) inhibition provides a metabolic lever to reinforce RAS-pathway inhibition for targeted PDAC treatment.

cancer biology↗

bioRxiv2021

Proteome biology of primary colorectal carcinoma and corresponding liver metastases

Colorectal adenocarcinomas (CRC) are one of the most commonly diagnosed tumors worldwide. Colorectal adenocarcinomas primarily metastasize into the liver and (less often) into the peritoneum. Patients suffering from CRC-liver metastasis (CRC-LM) typically present with a dismal overall survival compared to non-metastasized CRC patients. The metastasis process and metastasis-promoting factors in patients with CRC are under intensive debate. However, CRC studies investigating the proteome biology are lacking. Formalin-fixed paraffin-embedded (FFPE) tissue specimens provide a valuable resource for comprehensive proteomic studies of a broad variety of clinical malignancies. The presented pilot study compares the proteome of primary CRC and patient-matched CRC-LM. The applied protocol allows a reproducible and straightforward identification and quantification of over 2,600 proteins within the dissected tumorous tissue. Subsequent unsupervised clustering reveals distinct proteome biologies of the primary CRC and the corresponding CRC-LM. Statistical analysis yields multiple differentially abundant proteins in either primary CRC or their corresponding liver metastases. A more detailed analysis of dysregulated biological processes suggests an active immune response in the liver metastases, including several proteins of the complement system. Proteins with structural roles, e.g. cytoskeleton organization or cell junction assembly appear to be less prominent in liver metastases as compared to primary CRC. Immunohistochemistry corroborates proteomic high expression levels of metabolic proteins in CRC-LM. We further assessed how the in vitro inhibition of two in CRC-LM enriched metabolic proteins affected cell proliferation and chemosensitivity. The presented proteomic investigation in a small clinical cohort promotes a more comprehensive understanding of the distinct proteome biology of primary CRC and their corresponding liver metastases.

cancer biology↗

bioRxiv2021

Adaptive subsets limit the anti-tumoral NK-cell activity in Hepatocellular Carcinoma

Background and AimsHepatocellular carcinoma (HCC) is a global health burden with increasing incidence, poor prognosis and limited therapeutic options. Natural killer (NK) cells exhibit potent anti-tumoral activity and therefore represent potential targets for immunotherapeutic approaches in HCC treatment. However, the human NK-cell repertoire is highly diverse including conventional and adaptive NK cells that differ in phenotype and effector function. Adaptive NK-cell frequencies are increased in association with HCMV (human cytomegalovirus) seropositivity that is also common in HCC patients. In this study, we aimed to gain a better understanding of the NK-cell repertoire and the associated anti-tumoral activity in HCC patients. MethodsIn-depth phenotypic and functional flow-cytometry analyses of the HCMV-associated NK cell-repertoire obtained from 57 HCC patients, 33 liver cirrhosis patients and 36 healthy donors (HD). ResultsFirst, adaptive subsets are present in all three cohorts with conserved characteristics in patients with liver cirrhosis and HCC. Second, adaptive NK cells can be isolated from HCC tissue however lack features of tissue-residency and thus probably represent circulating/infiltrating lymphocytes. Third, the anti-tumoral activity by adaptive NK cells is reduced compared to conventional NK-cell subsets, also in HCC. Lastly, frequencies of adaptive NK cells were increased in patients suffering from Hepatitis B virus-associated HCC providing a link between etiology and the NK-cell repertoire in HCC. ConclusionAdaptive NK cells limit the anti-tumoral activitity of NK cells in HCC, especially in association with HBV infection that is accompanied by an expansion of this NK cell subset. Lay summaryIn patients with liver cancer (HCC), a subset of natural killer cells, so called adaptive NK cells show a diminished anti-tumoral activity compared to other, called conventional NK cells. Adaptive NK cells are expanded in patients with HCC associated to Hepatitis B virus infection. Thus, presence of adaptive NK cells contributes to the immune escape in HCC.

immunology↗