bims-stacyt 2026-01-18 papers

bioRxiv. 2026 Jan 06. pii: 2025.04.24.650538. [Epub ahead of print]

Separating food intake-dependent and -independent effects in cancer cachexia.

Yanshan Liang, Young-Yon Kwon, Sheng Hui.

Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle tissues, with diminished food intake due to anorexia commonly cited as a cause. However, to what extent reduced food intake drives these symptoms and other cachexia phenotypes, such as fatigue, remains generally unclear in preclinical models and patient populations. Here we demonstrate the critical need to address this question in cancer cachexia research. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and wasting of fat and muscle, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing fatigue. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.

DOI: https://doi.org/10.1101/2025.04.24.650538

Nat Metab. 2026 Jan 15.

Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer.

Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour-host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting.

DOI: https://doi.org/10.1038/s42255-025-01434-3

Biochem Pharmacol. 2026 Jan 14. pii: S0006-2952(26)00038-9. [Epub ahead of print] 117707

LIFR antagonism reverses epithelial pro-CAF programs in pancreatic ductal adenocarcinoma.

Cristina Di Giorgio, Maria Rosaria Sette, Benedetta Sensini, Eleonora Giannelli, Ginevra Lachi, Silvia Marchianò, Francesca Paniconi, Carmen Massa, Ginevra Urbani, Rosa De Gregorio, Valentina Sepe, Maria Chiara Monti, Federica Moraca, Bruno Catalanotti, Fabio Cartaginese, Eleonora Distrutti, Angela Zampella, Michele Biagioli, Stefano Fiorucci.

Extracellular matrix remodelling that occurs in pancreatic ductal adenocarcinoma (PDAC) is considered a promoting factor of cancer growth, immune evasion and therapeutic resistance. Cancer-associated fibroblasts (CAFs) that constitute the dominant stromal population, arise primarily from activated pancreatic stellate cells and display remarkable functional heterogeneity, encompassing inflammatory iCAFs and contractile myCAFs. Although epithelial-stromal communication is central to PDAC biology, the upstream mechanisms that prime tumour cells toward CAF-Activating cells remain incompletely defined. The leukaemia inhibitory factor (LIF), a pleiotropic cytokine of the IL-6 family, is highly expressed in PDAC and has been implicated in tumour progression. However, the role of LIF and LIF receptor (LIFR):gp130 complex in promoting CAF activation is poorly defined. Here, we combined human PDAC transcriptomics, immunofluorescence and epithelial-stromal co-culture assays to define LIF-driven pro-CAF programs and evaluate their pharmacological reversibility. In PDAC cancer cells, MIAPaCa-2 cells, LIF induced a coordinated transcriptional network encompassing inflammatory mediators, paracrine fibroblast-activating signals and ECM/mechanotransductive modules, while repressing stromal-inhibitory genes. These signatures were recapitulated in PDAC tissues, where LIF expression directly correlated with CAF markers and with stromal remodelling genes. On this background, we have developed a novel steroidal LIFR antagonist, LRI310, and evaluate its effects on LIF:LIFR axis. Exposure of PDCA cell lines to LRI310 suppresses STAT3 activation and counteracts effects of LIF on proliferation and CAF-inducing transcriptional programs. Collectively, these findings identify LIF as an important epithelial driver of CAF-oriented transcriptional programs in PDAC and support the development of LIFR antagonism as a promising strategy to modulate the desmoplastic microenvironment.

Keywords: Cancer-associated fibroblasts; Desmoplasia; JAK/STAT3; LIF/LIFR signalling; LIFR antagonists; Pancreatic ductal adenocarcinoma; Stromal activation

DOI: https://doi.org/10.1016/j.bcp.2026.117707

Apoptosis. 2026 Jan 12. 31(1): 42

Propofol attenuates angiogenesis by activating endoplasmic reticulum stress to suppress TFAP2C-driven VEGFA transcription.

Fan Yang, Yi Liu, Hui Li, Xue Shang, Qing Hua, Yun Zhu, Beibei Tao, Zhirong Sun.

During anesthesia, significant hemodynamic changes often alter the vascular microenvironment and affecting endothelial cell behavior. Propofol, a commonly used intravenous anesthetic, has been widely studied for its role in tumor angiogenesis through tumor cell-derived VEGF-mediated endothelial interactions. However, its direct effects on endothelial cell-mediated angiogenesis in non-malignant diseases such as diabetic retinopathy, diabetic nephropathy, and coronary heart disease remain unclear. To address this gap, we examined the effects of propofol on VEGFA-mediated angiogenesis in vitro and in vivo. Mechanistically, propofol triggers endoplasmic reticulum stress by promoting phosphorylation of PERK and its downstream effector eIF2α, leading to suppressed translation of TFAP2C-a transcription factor critical for endothelial function. Further analysis revealed that TFAP2C directly binds to the VEGFA promoter to activate its transcription, thereby facilitating VEGFA/VEGFR2-dependent angiogenesis. Together, these findings not only broaden the understanding of propofol's pharmacological profile, but also identify TFAP2C as a novel transcriptional regulator of VEGFA, offering new perspectives for therapeutic targeting of VEGFA-mediated angiogenesis.

Keywords: Angiogenesis; Endoplasmic reticulum stress; Propofol; TFAP2C; Transcription factor; VEGFA/VEGFR2

DOI: https://doi.org/10.1007/s10495-025-02214-w

Am J Physiol Cell Physiol. 2026 Jan 12.

Ablation of Tumor-Derived IGFBP-3 Attenuates Cancer-Associated Skeletal Muscle Wasting in Murine Pancreatic Cancer.

Zachary R Sechrist, Daniel J Belcher, Nidhi R Patel, Zoe J Pittman, Edward M Schwarz, Calvin L Cole.

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths, and its incidence is expected to rise. Skeletal muscle wasting (SMW) is a debilitating co-morbidity of PDAC with unknown etiology. Previously our lab demonstrated that systemic increases in Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) is associated with SMW and pathologic myocellular lipid accumulation in an orthotopic murine model of PDAC (Ptf1atm1-cre/+;Krastm4Tyj;Muc1-/-(KCKO)). Here we show that PDAC tumor cells secrete high levels of IGFBP-3 and that genetic ablation of IGFBP-3 in the KCKO and Ptf1atm1(cre)Cvw/WT;Krastm4Tyj/WT;Trp53tm5Tyj/tm5Tyj (KP2) orthotopic models of PDAC increases survival by at least 30 days in both models without affecting tumor progression. Mice with IGFBP-3-/- tumors lost 10- and 3-fold less appendicular lean mass, and experienced a 5- and 6-fold decrease in myocellular lipid accumulation vs mice with parental KCKO and KP2 tumors, respectively, at failure to thrive endpoints. Gene expression studies demonstrated increases in the ubiquitin proteasome pathway (fbxo32 and trim32), autophagy (ULK1 and LC3bII), and TGF-βR signaling (tgfβr1 and FoxO1) in skeletal muscle of mice inoculated with parental PDAC tumors, which was absent in mice with IGFBP-3-/- tumors. In vitro studies confirmed a role for IGFBP-3 in stimulating TGF-β receptors and regulating SMAD3 nuclear localization. Moreover, IGFBP-3 deletion in tumor cells and small molecule inhibition of TGF-βR1/2 attenuated myotube wasting. Collectively, these results suggest that PDAC derived IGFBP-3 promotes SMW via non-canonical binding of TGF-βRs, warranting formal investigation of IGFBP-3 as a potential therapeutic target for PDAC-related SMW through a novel pathway.

Keywords: Cancer Cachexia; IGFBP-3; PDAC; Skeletal Muscle

DOI: https://doi.org/10.1152/ajpcell.00421.2025