Activating mutations in KRAS are among the most frequent events in diverse human carcinomas and are particularly prominent in human pancreatic ductal adenocarcinoma (PDAC). An inducible ...KrasG12D-driven mouse model of PDAC has established a critical role for sustained KrasG12D expression in tumor maintenance, providing a model to determine the potential for and the underlying mechanisms of KrasG12D–independent PDAC recurrence. Here, we show that some tumors undergo spontaneous relapse and are devoid of KrasG12D expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1. Functional studies established the role of Yap1 and the transcriptional factor Tead2 in driving KrasG12D-independent tumor maintenance. The Yap1/Tead2 complex acts cooperatively with E2F transcription factors to activate a cell cycle and DNA replication program. Our studies, along with corroborating evidence from human PDAC models, portend a novel mechanism of escape from oncogenic Kras addiction in PDAC.
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•Spontaneous tumor recurs following oncogenic Kras extinction-induced tumor regression•Yap1 amplification drives Kras-independent tumor relapse in Tead2-dependent manner•Yap1/Tead2 cooperate with E2F in promoting a cell-cycle gene expression program•Most Kras-independent tumors resemble the quasimesenchymal subtype of human PDAC
In a mouse model of pancreatic cancer, amplification of Yap1 allows tumor cells to escape addiction to oncogenic Kras
Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to therapy lies within the ...heterogeneity of the tumor and its associated microenvironment. The vast diversity of cell states, composition of cells, and phenotypical characteristics makes it difficult to accurately classify GBM into distinct subtypes and find effective therapies. The advancement of sequencing technologies in recent years has further corroborated the heterogeneity of GBM at the single cell level. Recent studies have only begun to elucidate the different cell states present in GBM and how they correlate with sensitivity to therapy. Furthermore, it has become clear that GBM heterogeneity not only depends on intrinsic factors but also strongly differs between new and recurrent GBM, and treatment naïve and experienced patients. Understanding and connecting the complex cellular network that underlies GBM heterogeneity will be indispensable in finding new ways to tackle this deadly disease. Here, we present an overview of the multiple layers of GBM heterogeneity and discuss novel findings in the age of single cell technologies.
The biological functions and mechanisms of oncogenic KRASG12D (KRAS∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS∗ represses the ...expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS∗-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS∗-IRF2-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC.
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•Oncogenic KRAS promotes an immune-suppressive profile in CRC•IRF2 is a key downstream target of oncogenic KRAS-mediating immune suppression•IRF2 suppresses MDSC migration and infiltration by targeting the CXCL3-CXCR2 axis•Enforced IRF2 expression or CXCR2 inhibition overcomes anti-PD1 resistance in CRC
Liao et al. show that oncogenic KRAS represses IRF2 expression leading to high expression of CXCL3, which binds CXCR2 on MDSCs to promote their migration into the tumor microenvironment. Enforced IRF2 expression or CXCR2 blockade overcomes resistance of tumors expressing oncogenic KRAS to anti-PD-1 therapy.
Owing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with ...tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.
A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant ...prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b
Gr1
) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.
The ubiquitin-specific protease (USP) family is the largest group of cysteine proteases. Cancer genomic analysis identified frequent amplification of
(22%) in human pancreatic ductal adenocarcinoma ...(PDAC). USP21 overexpression correlates with human PDAC progression, and enforced expression of USP21 accelerates murine PDAC tumor growth and drives PanIN to PDAC progression in immortalized human pancreatic ductal cells. Conversely, depletion of USP21 impairs PDAC tumor growth. Mechanistically, USP21 deubiquitinates and stabilizes the TCF/LEF transcription factor TCF7, which promotes cancer cell stemness. Our work identifies and validates
as a PDAC oncogene, providing a potential druggable target for this intractable disease.
Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma ...cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.
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•PTEN deficiency in GBM drives macrophage infiltration via upregulation of LOX•LOX is directly regulated by YAP1 in PTEN-deficient GBM•LOX recruits macrophages into GBM via the β1 integrin-PYK2 pathway•LOX inhibition impairs PTEN-deficient GBM progression by decreasing TAM-derived SPP1
Chen et al. find that PTEN deficiency in glioblastoma (GBM) increases macrophage infiltration via a YAP1-LOX-β1 integrin-PYK2 axis, the infiltrated macrophages in turn secrete SPP1 to support GBM survival. In PTEN-null GBM xenograft mouse models, inhibition of LOX reduces macrophage infiltration and tumor growth.
Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC ...are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
G protein‐coupled estrogen receptor‐1 (GPER), a member of the G protein‐coupled receptor (GPCR) superfamily, mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. ...However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non‐BCSCs of three patient‐derived xenografts of ER−/PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER‐mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD‐Ser118 to sustain BCSC characteristics. Transfection with a dominant‐negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.
What's new?
G protein‐coupled estrogen receptor‐1 (GPER) mediates estrogen‐induced proliferation of normal and malignant breast epithelial cells. However, the role of GPER in breast cancer stem cells (BCSC) biology remains unclear. Here, using patient‐derived xenografts of ER–/PR+ breast cancer, the authors found higher expression of GPER in BCSCs than non‐BCSCs. Moreover, the results indicated that stemness features were sustained via GPER‐mediated PKA/BAD phosphorylation. Stimulation by the GPER ligand tamoxifen enhanced BCSC cell viability and population and BAD phosphorylation. The findings revealed a vital role of GPER‐mediated signaling pathways in BCSC survival, suggesting GPER as a potential therapeutic target for eradicating BCSCs.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to treat. It is refractory to most existing therapies, including immunotherapies, due to the presence of an excessive ...desmoplastic stroma, which restricts penetration of drugs and cytotoxic CD8+ T cells. Stromal modulation has shown promising results in the enhancement of immune checkpoint blockade treatment in PDAC. We demonstrate here effective stromal modulation by a polymeric micelle-based nanoformulation to codeliver a sonic hedgehog inhibitor (cyclopamine, abbreviated as CPA) and a cytotoxic chemotherapy drug (paclitaxel, abbreviated as PTX). The formulation, M-CPA/PTX, modulated the PDAC stroma by increasing the intratumoral vasculature density, which then promoted the tumor infiltration by cytotoxic CD8+ T cells without depletion of tumor-restraining α-smooth muscle action-positive fibroblasts and type I collage in the stroma. The combination of M-CPA/PTX and the PD-1 checkpoint blockade significantly prolonged animal survival in an orthotopic murine PDAC model as well as a genetically engineered mouse model of PDAC. The superior antitumor efficacy was mediated by enhanced tumor infiltration of CD8+ T cells without concomitant infiltration of suppressive regulatory T cells or myeloid-derived suppressor cells and by the coordinated action of PTX and interferon-gamma. Our results demonstrate that stroma-modulating nanoformulations are a promising approach to potentiate immune checkpoint blockade therapy of pancreatic cancer.
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