EGFR-activated myofibroblasts promote metastasis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified transforming growth factor beta (TGF-β) as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that epidermal growth factor receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-β in myCAFs through an autocrine process mediated by amphiregulin. Inhibition of this EGFR/ERBB2-signaling network in PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated myCAFs promote PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest that these processes might operate in other malignancies. These data provide functional relevance to myCAF heterogeneity and identify a candidate target for preventing tumor invasion in PDAC.

Journal Cancer Cell
Authors Gianluca Mucciolo et al
DATE 28 December 2023
Chance, ignorance, and the paradoxes of cancer: Richard Peto on developing preventative strategies under uncertainty

During the early 1980s both cancer biology and epidemiological methods were being transformed. In 1984 the leading cancer epidemiologist Richard Peto – who, in 1981, had published the landmark Causes of Cancer with Richard Doll – wrote a short chapter on “The need for ignorance in cancer research”, in which the worlds of epidemiology and speculative Darwinian biology met. His reflections on how evolutionary theory related to cancer have become known as “Peto’s paradox”, whilst his articulation of “black box epidemiology” provided the logic of subsequent practice in the field. We reprint this sparkling and prescient example of biologically-informed epidemiological theorising at its best in this issue of the European Journal of Epidemiology, together with four commentaries that focus on different aspects of its rich content. Here were provide some contextual background to the 1984 chapter, and our own speculations regarding various paradoxes in cancer epidemiology. We suggest that one reason for the relative lack of progress in indentifying novel modifiable causes of cancer over the last 40 years may reflect such exposures being ubiquitous within environments, and discuss the lessons for epidemiology that would follow from this.

Journal European Journal of Epidemiology
Authors George Davey Smith, Albert Hofman and Paul Brennan
DATE 26 December 2023
Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition

The conformational landscapes of peptide/human leucocyte antigen (pHLA) protein complexes encompassing tumor neoantigens provide a rationale for target selection towards autologous T cell, vaccine, and antibody-based therapeutic modalities. Here, using complementary biophysical and computational methods, we characterize recurrent RAS55-64 Q61 neoepitopes presented by the common HLA-A*01:01 allotype. We integrate sparse NMR restraints with Rosetta docking to determine the solution structure of NRASQ61K/HLA-A*01:01, which enables modeling of other common RAS55-64 neoepitopes. Hydrogen/deuterium exchange mass spectrometry experiments alongside molecular dynamics simulations reveal differences in solvent accessibility and conformational plasticity across a panel of common Q61 neoepitopes that are relevant for recognition by immunoreceptors. Finally, we predict binding and provide structural models of NRASQ61K antigens spanning the entire HLA allelic landscape, together with in vitro validation for HLA-A*01:191, HLA-B*15:01, and HLA-C*08:02. Our work provides a basis to delineate the solution surface features and immunogenicity of clinically relevant neoepitope/HLA targets for cancer therapy.

Team NexTGen
Journal Nature Communications
Authors Andrew C. McShan et al
DATE 11 December 2023
Structural principles of peptide-centric chimeric antigen receptor recognition guide therapeutic expansion

Peptide-centric chimeric antigen receptors (PC-CARs) recognize oncoprotein epitopes displayed by cell-surface human leukocyte antigens (HLAs) and offer a promising strategy for targeted cancer therapy. We have previously developed a PC-CAR targeting a neuroblastoma-associated PHOX2B peptide, leading to robust tumor cell lysis restricted by two common HLA allotypes. Here, we determine the 2.1-angstrom crystal structure of the PC-CAR–PHOX2B–HLA-A*24:02–β2m complex, which reveals the basis for antigen-specific recognition through interactions with CAR complementarity-determining regions (CDRs). This PC-CAR adopts a diagonal docking mode, where interactions with both conserved and polymorphic HLA framework residues permit recognition of multiple HLA allotypes from the A9 serological cross-reactive group, covering a combined global population frequency of up to 46.7%. Biochemical binding assays, molecular dynamics simulations, and structural and functional analyses demonstrate that high-affinity PC-CAR recognition of cross-reactive pHLAs necessitates the presentation of a specific peptide backbone, where subtle structural adaptations of the peptide are critical for high-affinity complex formation, and CAR T cell killing. Our results provide a molecular blueprint for engineering CARs with optimal recognition of tumor-associated antigens in the context of different HLAs, while minimizing cross-reactivity with self-epitopes.

Team NexTGen
Journal Science Immunology
Authors Yi Sun et al
DATE 01 December 2023
Bioinspired 3D microprinted cell scaffolds: Integration of graph theory to recapitulate complex network wiring in lymph nodes

Physical networks are ubiquitous in nature, but many of them possess a complex organizational structure that is difficult to recapitulate in artificial systems. This is especially the case in biomedical and tissue engineering, where the microstructural details of 3D cell scaffolds are important. Studies of biological networks—such as fibroblastic reticular cell (FRC) networks—have revealed the crucial role of network topology in a range of biological functions. However, cell scaffolds are rarely analyzed, or designed, using graph theory. To understand how networks affect adhered cells, 3D culture platforms capturing the complex topological properties of biologically relevant networks would be needed. In this work, we took inspiration from the small-world organization (high clustering and low path length) of FRC networks to design cell scaffolds. An algorithmic toolset was created to generate the networks and process them to improve their 3D printability. We employed tools from graph theory to show that the networks were small-world (omega factor, ω = -0.10 ± 0.02; small-world propensity, SWP = 0.74 ± 0.01). 3D microprinting was employed to physicalize networks as scaffolds, which supported the survival of FRCs. This work, therefore, represents a bioinspired, graph theory-driven approach to control the networks of microscale cell niches.

Team NexTGen
Journal Biotechnology Journal
Authors Matthew H. W. Chin et al
DATE 20 November 2023