Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities. In contrast, absence or depletion of GOF p53 leads to decreased origin firing and a higher frequency of fork collapse in isogenic cells, explaining their poorer proliferation rate. Following genome-wide analyses utilizing ChIP-Seq and RNA-Seq, GOF p53–induced origin firing, micronuclei formation, and fork protection were traced to the ability of GOF p53 to transactivate cyclin A and CHK1. Highlighting the therapeutic potential of CHK1’s role in GOF p53 dependency, experiments in cell culture and mouse xenografts demonstrated that inhibition of CHK1 selectively blocked proliferation of cells and tumors expressing GOF p53. Our data suggest the possibility that checkpoint inhibitors could efficiently and selectively target cancers expressing GOF p53 alleles.
Shilpa Singh, Catherine A. Vaughan, Rebecca A. Frum, Steven R. Grossman, Sumitra Deb, Swati Palit Deb
Worldwide epidemics of metabolic diseases, including liver steatosis, are associated with an increased frequency of malignancies, showing the highest positive correlation for liver cancer. The heterogeneity of liver cancer represents a clinical challenge. In liver, the transcription factor PPARγ promotes metabolic adaptations of lipogenesis and aerobic glycolysis under the control of Akt2 activity, but the role of PPARγ in liver tumorigenesis is unknown. Here we have combined preclinical mouse models of liver cancer and genetic studies of a human liver biopsy atlas with the aim of identifying putative therapeutic targets in the context of liver steatosis and cancer. We have revealed a protumoral interaction of Akt2 signaling with hepatocyte nuclear factor 1α (HNF1α) and PPARγ, transcription factors that are master regulators of hepatocyte and adipocyte differentiation, respectively. Akt2 phosphorylates and inhibits HNF1α, thus relieving the suppression of hepatic PPARγ expression and promoting tumorigenesis. Finally, we observed that pharmacological inhibition of PPARγ is therapeutically effective in a preclinical murine model of steatosis-associated liver cancer. Taken together, our studies in humans and mice reveal that Akt2 controls hepatic tumorigenesis through crosstalk between HNF1α and PPARγ.
Cecilia Patitucci, Gabrielle Couchy, Alessia Bagattin, Tatiana Cañeque, Aurélien de Reyniès, Jean-Yves Scoazec, Raphaël Rodriguez, Marco Pontoglio, Jessica Zucman-Rossi, Mario Pende, Ganna Panasyuk
The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4–ENL–P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (
Hiroshi Okuda, Boban Stanojevic, Akinori Kanai, Takeshi Kawamura, Satoshi Takahashi, Hirotaka Matsui, Akifumi Takaori-Kondo, Akihiko Yokoyama
Paradoxically, during early tumor development in many cancer types, TGF-β acts as a tumor suppressor, whereas in the advanced stages of these cancers, increased TGF-β expression is linked to high metastasis and poor prognosis. These findings suggest that unidentified mechanisms may function to rewire TGF-β signaling toward its prometastatic role in cancer cells. Our current study using non–small-cell lung carcinoma (NSCLC) cell lines, animal models, and clinical specimens demonstrates that suppression of SMAD2, with SMAD3 function intact, switches TGF-β–induced transcriptional responses to a prometastatic state. Importantly, we identified chaperonin containing TCP1 subunit 6A (CCT6A) as an inhibitor and direct binding protein of SMAD2 and found that CCT6A suppresses SMAD2 function in NSCLC cells and promotes metastasis. Furthermore, selective inhibition of SMAD3 or CCT6A efficiently suppresses TGF-β–mediated metastasis. Our findings provide a mechanism that directs TGF-β signaling toward its prometastatic arm and may contribute to the development of therapeutic strategies targeting TGF-β for NSCLC.
Zhe Ying, Han Tian, Yun Li, Rong Lian, Wei Li, Shanshan Wu, Hui-Zhong Zhang, Jueheng Wu, Lei Liu, Junwei Song, Hongyu Guan, Junchao Cai, Xun Zhu, Jun Li, Mengfeng Li
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel–Lindau (
Arimichi Okazaki, Paulo A. Gameiro, Danos Christodoulou, Laura Laviollette, Meike Schneider, Frances Chaves, Anat Stemmer-Rachamimov, Stephanie A. Yazinski, Richard Lee, Gregory Stephanopoulos, Lee Zou, Othon Iliopoulos
Mutations in the isocitrate dehydrogenase genes
Gary Kohanbash, Diego A. Carrera, Shruti Shrivastav, Brian J. Ahn, Naznin Jahan, Tali Mazor, Zinal S. Chheda, Kira M. Downey, Payal B. Watchmaker, Casey Beppler, Rolf Warta, Nduka A. Amankulor, Christel Herold-Mende, Joseph F. Costello, Hideho Okada
Loss of phosphatase and tensin homolog (PTEN) and activation of the PI3K/AKT signaling pathway are hallmarks of prostate cancer (PCa). However, these alterations alone are insufficient for cells to acquire metastatic traits. Here, we have shown that the histone dimethyl transferase WHSC1 critically drives indolent PTEN-null tumors to become metastatic PCa. In a PTEN-null murine PCa model, WHSC1 overexpression in prostate epithelium cooperated with
Ni Li, Wei Xue, Huairui Yuan, Baijun Dong, Yufeng Ding, Yongfeng Liu, Min Jiang, Shan Kan, Tongyu Sun, Jiale Ren, Qiang Pan, Xiang Li, Peiyuan Zhang, Guohong Hu, Yan Wang, Xiaoming Wang, Qintong Li, Jun Qin
The most frequent focal alterations in human retinoblastoma are mutations in the tumor-suppressor gene retinoblastoma (
Nan Wu, Deshui Jia, Breanna Bates, Ryan Basom, Charles G. Eberhart, David MacPherson
Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.
Paul A. Beavis, Melissa A. Henderson, Lauren Giuffrida, Jane K. Mills, Kevin Sek, Ryan S. Cross, Alexander J. Davenport, Liza B. John, Sherly Mardiana, Clare Y. Slaney, Ricky W. Johnstone, Joseph A. Trapani, John Stagg, Sherene Loi, Lev Kats, David Gyorki, Michael H. Kershaw, Phillip K. Darcy
Elevated expression of the chemokine receptor CCR4 in tumors is associated with poor prognosis in several cancers. Here, we have determined that CCR4 was highly expressed in human renal cell carcinoma (RCC) biopsies and observed abnormal levels of CCR4 ligands in RCC patient plasma. An antagonistic anti-CCR4 antibody had antitumor activity in the RENCA mouse model of RCC. CCR4 inhibition did not reduce the proportion of infiltrating leukocytes in the tumor microenvironment but altered the phenotype of myeloid cells, increased NK cell and Th1 cytokine levels, and reduced immature myeloid cell infiltrate and blood chemokine levels. In spite of prominent changes in the myeloid compartment, the anti-CCR4 antibody did not affect RENCA tumors in T cell–deficient mice, and treatment with an anti–class II MHC antibody abrogated its antitumor activity. We concluded that the effects of the anti-CCR4 antibody required the adaptive immune system and CD4+ T cells. Moreover, CCL17-induced IFN-γ production was reduced when Th1-polarized normal CD4+ T cells were exposed to the CCR4 ligand, evidencing the involvement of CCR4 in Th1/Th2 regulation. The anti-CCR4 antibody, alone or in combination with other immune modulators, is a potential treatment approach to human solid cancers with high levels of CCR4-expressing tumor-infiltrating leukocytes and abnormal plasma CCR4 ligand levels.
Chiara Berlato, Moddasar N. Khan, Tiziana Schioppa, Richard Thompson, Eleni Maniati, Anne Montfort, Maryam Jangani, Monica Canosa, Hagen Kulbe, Urs B. Hagemann, Alexander R. Duncan, Laura Fletcher, Robert W. Wilkinson, Thomas Powles, Sergio A. Quezada, Frances R. Balkwill