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Metabolic heterogeneity confers differences in melanoma metastatic potential 期刊论文
NATURE, 2020, 577 (7788) : 115-+
作者:  Tasdogan, Alpaslan;  Faubert, Brandon;  Ramesh, Vijayashree;  Ubellacker, Jessalyn M.;  Shen, Bo;  Solmonson, Ashley;  Murphy, Malea M.;  Gu, Zhimin;  Gu, Wen;  Martin, Misty;  Kasitinon, Stacy Y.;  Vandergriff, Travis;  Mathews, Thomas P.;  Zhao, Zhiyu;  Schadendorf, Dirk;  DeBerardinis, Ralph J.;  Morrison, Sean J.
收藏  |  浏览/下载:29/0  |  提交时间:2020/07/03

Metastasis requires cancer cells to undergo metabolic changes that are poorly understood(1-3). Here we show that metabolic differences among melanoma cells confer differences in metastatic potential as a result of differences in the function of the MCT1 transporter. In vivo isotope tracing analysis in patient-derived xenografts revealed differences in nutrient handling between efficiently and inefficiently metastasizing melanomas, with circulating lactate being a more prominent source of tumour lactate in efficient metastasizers. Efficient metastasizers had higher levels of MCT1, and inhibition of MCT1 reduced lactate uptake. MCT1 inhibition had little effect on the growth of primary subcutaneous tumours, but resulted in depletion of circulating melanoma cells and reduced the metastatic disease burden in patient-derived xenografts and in mouse melanomas. In addition, inhibition of MCT1 suppressed the oxidative pentose phosphate pathway and increased levels of reactive oxygen species. Antioxidants blocked the effects of MCT1 inhibition on metastasis. MCT1(high) and MCT1(-/low) cells from the same melanomas had similar capacities to form subcutaneous tumours, but MCT1(high) cells formed more metastases after intravenous injection. Metabolic differences among cancer cells thus confer differences in metastatic potential as metastasizing cells depend on MCT1 to manage oxidative stress.


  
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I 期刊论文
NATURE, 2020, 581 (7806) : 100-+
作者:  Waszak, Sebastian M.;  Robinson, Giles W.;  Gudenas, Brian L.;  Smith, Kyle S.;  Forget, Antoine;  Kojic, Marija;  Garcia-Lopez, Jesus;  Hadley, Jennifer;  Hamilton, Kayla V.;  Indersie, Emilie;  Buchhalter, Ivo;  Kerssemakers, Jules;  Jager, Natalie;  Sharma, Tanvi;  Rausch, Tobias;  Kool, Marcel;  Sturm, Dominik;  Jones, David T. W.;  Vasilyeva, Aksana;  Tatevossian, Ruth G.;  Neale, Geoffrey;  Lombard, Berangere;  Loew, Damarys;  Nakitandwe, Joy;  Rusch, Michael;  Bowers, Daniel C.;  Bendel, Anne;  Partap, Sonia;  Chintagumpala, Murali;  Crawford, John;  Gottardo, Nicholas G.;  Smith, Amy;  Dufour, Christelle;  Rutkowski, Stefan;  Eggen, Tone;  Wesenberg, Finn;  Kjaerheim, Kristina;  Feychting, Maria;  Lannering, Birgitta;  Schuz, Joachim;  Johansen, Christoffer;  Andersen, Tina V.;  Roosli, Martin;  Kuehni, Claudia E.;  Grotzer, Michael;  Remke, Marc;  Puget, Stephanie;  Pajtler, Kristian W.;  Milde, Till;  Witt, Olaf;  Ryzhova, Marina;  Korshunov, Andrey;  Orr, Brent A.;  Ellison, David W.;  Brugieres, Laurence;  Lichter, Peter;  Nichols, Kim E.;  Gajjar, Amar;  Wainwright, Brandon J.;  Ayrault, Olivier;  Korbel, Jan O.;  Northcott, Paul A.;  Pfister, Stefan M.
收藏  |  浏览/下载:61/0  |  提交时间:2020/07/03

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1-3). However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found(5) despite the frequent downregulation of MHC-I expression(6-8). Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Inhibition of the autophagy-lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8(+) T cells.


  
CRISPR screen in regulatory T cells reveals modulators of Foxp3 期刊论文
NATURE, 2020
作者:  Xu, Daqian;  Wang, Zheng;  Xia, Yan;  Shao, Fei;  Xia, Weiya;  Wei, Yongkun;  Li, Xinjian;  Qian, Xu;  Lee, Jong-Ho;  Du, Linyong;  Zheng, Yanhua;  Lv, Guishuai;  Leu, Jia-shiun;  Wang, Hongyang;  Xing, Dongming;  Liang, Tingbo;  Hung, Mien-Chie;  Lu, Zhimin
收藏  |  浏览/下载:49/0  |  提交时间:2020/07/03

Regulatory T (T-reg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity(1). Conversely, T-reg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties(2), can promote autoimmunity and/or facilitate more effective tumour immunity(3,4). A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective T-reg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse T-reg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression  whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. T-reg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient T-reg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in T-reg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for T-reg immunotherapies for cancer and autoimmune disease.


A CRISPR-based screening platform was used to identify previously uncharacterized genes that regulate the regulatory T cell-specific master transcription factor Foxp3, indicating that this screening method may be broadly applicable for the discovery of other genes involved in autoimmunity and immune responses to cancer.


  
Dietary modifications for enhanced cancer therapy 期刊论文
NATURE, 2020, 579 (7800) : 507-517
作者:  Keller, Matthew D.;  Ching, Krystal L.;  Liang, Feng-Xia;  Dhabaria, Avantika;  Tam, Kayan;  Ueberheide, Beatrix M.;  Unutmaz, Derya;  Torres, Victor J.;  Cadwell, Ken
收藏  |  浏览/下载:27/0  |  提交时间:2020/07/03

Tumours depend on nutrients supplied by the host for their growth and survival. Modifications to the host'  s diet can change nutrient availability in the tumour microenvironment, which might represent a promising strategy for inhibiting tumour growth. Dietary modifications can limit tumour-specific nutritional requirements, alter certain nutrients that target the metabolic vulnerabilities of the tumour, or enhance the cytotoxicity of anti-cancer drugs. Recent reports have suggested that modification of several nutrients in the diet can alter the efficacy of cancer therapies, and some of the newest developments in this quickly expanding field are reviewed here. The results discussed indicate that the dietary habits and nutritional state of a patient must be taken into account during cancer research and therapy.


  
The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis 期刊论文
NATURE, 2020, 580 (7804) : 530-+
作者:  Erler, Janine T.;  Bennewith, Kevin L.;  Nicolau, Monica;  Dornhofer, Nadja;  Kong, Christina;  Le, Quynh-Thu;  Chi, Jen-Tsan Ashley;  Jeffrey, Stefanie S.;  Giaccia, Amato J.
收藏  |  浏览/下载:45/0  |  提交时间:2020/07/03

Phosphorylation of INSIG1 and INSIG2 by PCK1 leads to a reduction in the binding of sterols, the activation of SREBP1 and SREBP2 and the downstream transcription of lipogenesis-associated genes that promote tumour growth.


Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP-SREBP complex from the endoplasmic reticulum and the activation of SREBPs(1,2). However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol-and in particular, whether oncogenic signalling has a role-is unclear. Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.


  
CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities 期刊论文
NATURE, 2020
作者:  Yang, Jianfeng;  Faccenda, Manuele
收藏  |  浏览/下载:23/0  |  提交时间:2020/07/03

Cancer genomics studies have identified thousands of putative cancer driver genes(1). Development of high-throughput and accurate models to define the functions of these genes is a major challenge. Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif(2) from the alpha-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities.


CRISPR screens in a 3D spheroid cancer model system more accurately recapitulate cancer phenotypes than existing 2D models and were used to identify carboxypeptidase D, acting via the IGF1R, as a 3D-specific driver of cancer growth.


  
Gasdermin E suppresses tumour growth by activating anti-tumour immunity 期刊论文
NATURE, 2020
作者:  Maroju, Praveen Kumar;  Grazioli, Cesare;  Di Fraia, Michele;  Moioli, Matteo;  Ertel, Dominik;  Ahmadi, Hamed;  Plekan, Oksana;  Finetti, Paola;  Allaria, Enrico;  Giannessi, Luca;  De Ninno, Giovanni;  Spezzani, Carlo;  Penco, Giuseppe;  Spampinati, Simone;  Demidovich, Alexander
收藏  |  浏览/下载:61/0  |  提交时间:2020/07/03

Cleavage of the gasdermin proteins to produce pore-forming amino-terminal fragments causes inflammatory cell death (pyroptosis)(1). Gasdermin E (GSDME, also known as DFNA5)-mutated in familial ageing-related hearing loss(2)-can be cleaved by caspase 3, thereby converting noninflammatory apoptosis to pyroptosis in GSDME-expressing cells(3-5). GSDME expression is suppressed in many cancers, and reduced GSDME levels are associated with decreased survival as a result of breast cancer(2,6), suggesting that GSDME might be a tumour suppressor. Here we show that 20 of 22 tested cancer-associated GSDME mutations reduce GSDME function. In mice, knocking out Gsdme in GSDME-expressing tumours enhances, whereas ectopic expression in Gsdme-repressed tumours inhibits, tumour growth. This tumour suppression is mediated by killer cytotoxic lymphocytes: it is abrogated in perforin-deficient mice or mice depleted of killer lymphocytes. GSDME expression enhances the phagocytosis of tumour cells by tumour-associated macrophages, as well as the number and functions of tumour-infiltrating natural-killer and CD8(+) T lymphocytes. Killer-cell granzyme B also activates caspase-independent pyroptosis in target cells by directly cleaving GSDME at the same site as caspase 3. Uncleavable or pore-defective GSDME proteins are not tumour suppressive. Thus, tumour GSDME acts as a tumour suppressor by activating pyroptosis, enhancing anti-tumour immunity.


The gasdermin E protein is shown to act as a tumour suppressor: it is cleaved by caspase 3 and granzyme B and leads to pyroptosis of cancer cells, provoking an immune response to the tumour.


  
Epigenetic therapy inhibits metastases by disrupting premetastatic niches 期刊论文
NATURE, 2020, 579 (7798) : 284-+
作者:  Mehta, Vedanta;  Pang, Kar-Lai;  Rozbesky, Daniel;  Nather, Katrin;  Keen, Adam;  Lachowski, Dariusz;  Kong, Youxin;  Karia, Dimple;  Ameismeier, Michael;  Huang, Jianhua;  Fang, Yun;  del Rio Hernandez, Armando;  Reader, John S.;  Jones, E. Yvonne;  Tzima, Ellie
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

Cancer recurrence after surgery remains an unresolved clinical problem(1-3). Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites(4-6). There are currently no effective interventions that prevent the formation of the premetastatic microenvironment(6,7). Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.


  
Loss of p53 drives neuron reprogramming in head and neck cancer 期刊论文
NATURE, 2020, 578 (7795) : 449-+
作者:  Lipson, Mark;  39;ane
收藏  |  浏览/下载:30/0  |  提交时间:2020/07/03

MicroRNAs from head and neck cancer cells, shuttled to sensory neurons by extracellular vesicles, cause a shift to an adrenergic neuronal phenotype that promotes tumour progression.


The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system(1,2). Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown(1,3). Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.


  
ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity 期刊论文
NATURE, 2020
作者:  Papai, Gabor;  Frechard, Alexandre;  Kolesnikova, Olga;  Crucifix, Corinne;  Schultz, Patrick;  Ben-Shem, Adam
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

Tumour-infiltrating group 2 innate lymphoid cells prime CD8(+) T cells and amplify the anti-tumour effects of PD-1 blockade in pancreatic ductal adenocarcinoma.


Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues(1,2). Although ILC2s are found in cancers of these tissues(3), their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8(+) T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1(+) TILC2s and PD-1(+) T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.