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Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis., (© 2024. The Author(s).)

Uncovering whether convergent adaptations share a genetic basis is consequential for understanding the evolution of phenotypic diversity. This information can help us understand the extent to which shared ancestry or independent evolution shape adaptive phenotypes. In this study, we first ask whether the same genes underlie polymorphic mimicry in Papilio swallowtail butterflies. By comparing signatures of genetic variation between polymorphic and monomorphic species, we then investigate how ancestral variation, hybridization, and independent evolution contributed to wing pattern diversity in this group. We report that a single gene, doublesex (dsx), controls mimicry across multiple taxa, but with species-specific patterns of genetic differentiation and linkage disequilibrium. In contrast to widespread examples of phenotypic evolution driven by introgression, our analyses reveal distinct mimicry alleles. We conclude that mimicry evolution in this group was likely facilitated by ancestral polymorphism resulting from early co-option of dsx as a mimicry locus, and that evolutionary turnover of dsx alleles may underlie the wing pattern diversity of extant polymorphic and monomorphic lineages.

The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.

Membrane-bound CD40L (mCD40L) but not soluble CD40L (sCD40L) has been implicated in direct cell death induction and apoptosis in CD40-expressing carcinomas. In this study, we show that mCD40L but not sCD40L induces NORE1A/Rassf5 expression in an NFκB-dependant mechanism. NORE1A expression appeared to contribute to mCD40L-induced cell death and enhance cell transition from G1 to S phase of the cell cycle in a p21-dependent mechanism. The upregulation of p21 protein was attributed to NORE1A expression, since NORE1A inhibition resulted in p21 downregulation. p21 upregulation was concomitant with lower p53 expression in the cytoplasmic fraction with no detectable increase at the nuclear p53 level. Moreover, mCD40L-induced cell death mediated by NORE1A expression appeared to be independent of mCD40L-induced cell death mediated by sustained JNK activation since NORE1A inhibition did not affect JNK phosphorylation and vice versa. The presented data allow better understanding of the mechanism by which mCD40L induces cell death which could be exploited in the clinical development of CD40-targeted anti-cancer therapies.

CD40-induced signalling through ligation with its natural ligand (CD40L/CD154) is dependent on recruitment of TRAF molecules to the cytoplasmic domain of the receptor. Here, we applied the yeast two-hybrid system to examine whether other proteins can interact with CD40. Fas-Associated Factor 1(FAF1) was isolated from a HeLa cDNA library using the CD40 cytoplasmic tail (216-278 aa) as a bait construct. FAF1 was able to interact with CD40 both in vitro and in vivo. The FAF1 N-terminal domain was sufficient to bind CD40 and required the TRAF6-binding domain within the cytoplasmic tail of CD40 for binding. CD40 ligation induced FAF1 expression in an NFκB-dependent manner. Knockdown of FAF1 prolonged CD40-induced NFκB, whereas overexpression of FAF1 suppressed CD40-induced NFκB activity and this required interaction of FAF1 with the CD40 receptor via its FID domain. Thus, we report a novel role for FAF1in regulating CD40-induced NFκB activation via a negative feedback loop. Loss of FAF1 function in certain human malignancies may contribute to oncogenesis through unchecked NFκB activation, and further understanding of this process may provide a biomarker of NFκB-targeted therapies for such malignancies.