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KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of PDAC. The involvement of cell death pathways in the early stage of pancreatic ductal adenocarcinoma (PDAC) development, especially KRAS-dependent acinar-to-ductal metaplasia (ADM), remains to be investigated. Here, the authors find that TAK1 mediates cell survival during ADM transdifferentiation through suppression of apoptosis and necroptosis, which could be targeted for prevention and treatment of PDAC.

Reprogramming of the cellular metabolism is a hallmark of pancreatic cancer, yet it remains unclear at what stage during carcinogenesis it occurs. Here, we investigated the metabolic requirements for acinar-to-ductal metaplasia (ADM), the first step in pancreatic carcinogenesis. We detected increased glycolytic marker expression in human ADM suggesting that a metabolic switch occurs during ADM formation. We report that this switch was similarly required for ADM formation in different oncogenic mouse models (KRAS, PI3K, and MEK1) and in ligand-induced ADM in mouse wild-type acini. In addition, we show that a functional electron transport chain (ETC), but not mitochondrial ATP production, was essential to ADM formation. We conclude that the ETC provides NAD+ for the de novo synthesis of serine from glycolysis intermediates. Our findings demonstrate that metabolic programming is essential for the initiation of pancreatic carcinogenesis and thus identifies potential targets for metabolic intervention.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Added substantial data concerning serine importance

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1’s role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of Wnt/β-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts (TAF) and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with HIF-1α, arguing for an importance of hypoxia-independent, i.e., non-canonical, HIF-1 stabilization for intestinal tumorigenesis that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1 and suggests that hypoxia and HIF-1α stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.

River surfing has evolved from natural rivers to artificial standing waves, like the Fuchslochwelle in Nuremberg, where optimizing wave quality and safety remains a challenge. Key issues include recirculation zones that pose risks, particularly at higher inflows. This study addresses safety and performance improvements by introducing geometric modifications to reduce recirculation zones. Using STAR-CCM+ simulations, 16 configurations of baffles and inlays were analyzed. A 3D-CAD model of the Fuchslochwelle was developed to test symmetrical and asymmetrical configurations, focusing on reducing vorticity. Results showed that baffles placed 2 m from the inlay reduced recirculation zones by over 50%. Asymmetrical setups, combining wall and inlay baffles, also proved effective. Following simulations, a baffle was installed at 3 m, enhancing safety and quality. Previously, inflows above 7.5 m3/s caused dangerous backflow, requiring surfers to swim or dive to escape turbulence. With the baffle, safe operation increased to 9 m3/s, a 20% improvement, making the system suitable for surfers of all skill levels. These finding provide a novel approach to enhancing flow dynamics, applicable to a wide range of artificial standing waves. The valuable insights gained enable operators to optimize the dynamics and accessibility through geometric modifications while ensuring safety for users.

The hypoxia-inducible transcription factor HIF-1 is appreciated as a promising target for cancer therapy. However, conditional deletion of HIF-1 and HIF-1 target genes in cells of the tumor microenvironment can result in accelerated tumor growth, calling for a detailed characterization of the cellular context to fully comprehend HIF-1's role in tumorigenesis. We dissected cell type-specific functions of HIF-1 for intestinal tumorigenesis by lineage-restricted deletion of the Hif1a locus. Intestinal epithelial cell-specific Hif1a loss reduced activation of wnt/b-catenin, tumor-specific metabolism and inflammation, significantly inhibiting tumor growth. Deletion of Hif1a in myeloid cells reduced the expression of fibroblast-activating factors in tumor-associated macrophages resulting in decreased abundance of tumor-associated fibroblasts and robustly reduced tumor formation. Interestingly, hypoxia was detectable only sparsely and without spatial association with nuclear HIF-1a in intestinal adenomas, pointing towards a functional importance of hypoxia-independent, i.e. non-canonical HIF-1 stabilization that has not been previously appreciated. This adds a further layer of complexity to the regulation of HIF-1a and suggests that hypoxia and HIF-1a stabilization can be uncoupled in cancer. Collectively, our data show that HIF-1 is a pivotal pro-tumorigenic factor for intestinal tumor formation, controlling key oncogenic programs in both the epithelial tumor compartment and the tumor microenvironment.