Disruption of the Clock Component Bmal1 in Mice Promotes Cancer Metastasis through the PAI-1-TGF-beta-myoCAF-Dependent Mechanism

The circadian clock in animals and humans plays crucial roles in multiple physiological processes. Disruption of circadian homeostasis causes detrimental effects. Here, it is demonstrated that the disruption of the circadian rhythm by genetic deletion of mouse brain and muscle ARNT-like 1 (Bmal1) gene, coding for the key clock transcription factor, augments an exacerbated fibrotic phenotype in various tumors. Accretion of cancer-associated fibroblasts (CAFs), especially the alpha smooth muscle actin positive myoCAFs, accelerates tumor growth rates and metastatic potentials. Mechanistically, deletion of Bmal1 abrogates expression of its transcriptionally targeted plasminogen activator inhibitor-1 (PAI-1). Consequently, decreased levels of PAI-1 in the tumor microenvironment instigate plasmin activation through upregulation of tissue plasminogen activator and urokinase plasminogen activator. The activated plasmin converts latent TGF-beta into its activated form, which potently induces tumor fibrosis and the transition of CAFs into myoCAFs, the latter promoting cancer metastasis. Pharmacological inhibition of the TGF-beta signaling largely ablates the metastatic potentials of colorectal cancer, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma. Together, these data provide novel mechanistic insights into disruption of the circadian clock in tumor growth and metastasis. It is reasonably speculated that normalization of the circadian rhythm in patients provides a novel paradigm for cancer therapy.Funding Agencies|European Research Council (ERC) advanced grant ANGIOFAT [250021]; Swedish Research Council; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute Foundation; Karolinska Institute distinguished professor award; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grant; NOVO Nordisk Foundation; Knut and Alice Wallenbergs Foundation; Robert Lundberg Memorial Foundation [2021-00668]; National Key R &amp; D Program of China [2020YFC0846600]; Volkswagen Stiftung</p

Asymmetric Desymmetrization of 1,3-Diketones via Intramolecular Benzoin Reaction

A general method for the asymmetric desymmetrization of 1,3-diketone substrates via chiral N-heterocyclic carbene catalyzed intramolecular benzoin reactions was developed. Five- and six-membered cyclic ketones bearing two contiguous fully substituted stereocenters were generated with excellent diastereoselectivities and moderate to excellent enantioselectivities

Interleukin-33 is a Novel Immunosuppressor that Protects Cancer Cells from TIL Killing by a Macrophage-Mediated Shedding Mechanism

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell-mediated cancer killing. However, this process can be affected by other non-cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin-33 (IL-33)-activated macrophages protect melanoma cells from tumor-infiltrating lymphocyte-mediated killing. Mechanistically, IL-33 markedly upregulates metalloprotease 9 (MMP-9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and gamma delta T cells. Further, MMP-9 also cleaves the MHC class I molecule, cell surface antigen-presenting complex molecules, expressed in melanoma cells. Consequently, IL-33-induced macrophage MMP-9 robustly mitigates the tumor killing-effect by T cells. Genetic and pharmacological loss-of-function of MMP-9 sheddase restore T cell-mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL-33-macrophage-MMP-9 axis-mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL-33 and MMP-9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy.Funding Agencies|European Research Council (ERC) advanced grant ANGIOFATEuropean Research Council (ERC) [250021]; Swedish Research CouncilSwedish Research CouncilEuropean Commission; Swedish Cancer Foundation; Swedish Childrens Cancer Foundation; Strategic Research Areas (SFO)-Stem Cell and Regenerative Medicine Foundation; Karolinska Institute FoundationKarolinska Institutet; Karolinska Institute distinguished professor awardKarolinska Institutet; Torsten Soderbergs Foundation; Maud and Birger Gustavsson Foundation; NOVO Nordisk Foundation-Advance grantNovo Nordisk; NOVO Nordisk FoundationNovo Nordisk Foundation; Knut and Alice Wallenbergs FoundationKnut &amp; Alice Wallenberg Foundation; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81801163, 81703617]; Jinan clinical medical science and technology innovation plan [202019099]; China Scholarship CouncilChina Scholarship Council [201906225024]; Karolinska InstituteKarolinska Institutet</p

Inflammatory cell-derived CXCL3 promotes pancreatic cancer metastasis through a novel myofibroblast-hijacked cancer escape mechanism

Objective:Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy. Design: Two unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models. Results: IL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis. Conclusions: Our work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer

Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors

Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels

Patient-derived organoids as personalized avatars and a potential immunotherapy model in cervical cancer

Summary: Cervical cancer remains a significant health issue in developing countries. However, finding a preclinical model that accurately reproduces tumor characteristics is challenging. Therefore, we established a patient-derived organoids (PDOs) biobank containing 67 cases of heterogeneous cervical cancer that mimic the histopathological and genomic characteristics of parental tumors. The in vitro response of the organoids indicated their ability to capture the radiological heterogeneity of the patients. To model individual responses to adoptive T cell therapy (ACT), we expanded tumor-infiltrating lymphocytes (TILs) ex vivo and co-cultured them with paired organoids. The PDOs-TILs co-culture system demonstrates clear responses that correspond to established immunotherapy efficiency markers like the proportion of CTLs. This study supports the potential of the PDOs platform to guide treatment in prospective interventional trials in cervical cancer