How one rogue cell becomes a tumor
Cancer starts with a single cell that acquires mutations in its DNA. These mutations may be inherited from one’s parents or may result from exposure to radiation, cigarette smoke or dietary components.
Mutations may intensify the messages a cell uses to grow or eliminate the signals it uses to stop growing or die. The mutant cell begins to divide too often and loses the ability to die, eventually giving rise to a mass of cells we call a tumor. Identifying the mutations, signals and mechanisms that promote and sustain cell growth and suppress cell death creates new opportunities to target human cancer.
Although tumors arise from a single cell, as this cell divides it gives rise to many different kinds of cells. This heterogeneity makes cancers particularly challenging to treat: a drug that kills some tumor cells may have no impact on others, and the resistant cells may end up taking over the mass. Understanding tumor heterogeneity and finding ways to overcome it is a major goal of research in the Tumor Initiation and Maintenance program.
We’ve brought together scientists with expertise in developmental and stem cell biology with investigators who focus on epigenetics and the signaling pathways that regulate cell growth and fate. The diversity of our faculty members, along with our shared interests in what drives cancer growth, is fostering strong interactions that lead to breakthrough discoveries and consequently, treatments for cancers of the blood, brain, breast and pancreas.
– Robert Wechsler-Reya, Ph.D., Program Director
Pancreatic ductal adenocarcinoma (PDAC) has relatively few blood vessels, and as a result, often expresses high levels of hypoxia inducible factor 1 alpha (HIF1A), a protein that allows cells to survive under low-oxygen conditions. Anindya Bagchi and colleagues speculated that HIF1A might be required for tumor growth, but when they eliminated HIF1A in their animal models of pancreatic cancer, the tumors actually became more aggressive, and exhibited increased metastasis. This effect was driven by upregulation of a protein called PPP1R1B, which in turn caused degradation of a critical tumor suppressor protein called p53. Importantly, the group showed that inhibition of PPP1R1B significantly reduced the ability of PDAC cells to form metastases in mice. These findings indicate that HIF1A can act as a tumor suppressor and provide insight into mechanisms regulating pancreatic cancer invasion and metastasis. Video
Medulloblastoma is a highly malignant brain tumor that occurs predominantly in children. Recent studies have shown that medulloblastoma patients are very heterogenous, but despite this, most patients receive the same therapies, and many end up dying of their disease. Robert Wechsler-Reya and colleagues hypothesized that tailoring therapy based on the characteristics of each patient’s tumor might improve outcomes. To test this, they subjected tumor cells from 20 medulloblastoma patients to DNA sequencing, gene expression profiling, and high-throughput drug screening, and used the results to identify the most effective therapies. Importantly, they found that each patient’s cells were sensitive to a distinct set of drugs, and that drug screening could help identify novel therapies for some of the most aggressive cancers. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor.
A subset of leukemias is driven by chromosomal alterations that fuse the AF10 gene to genes on other chromosomes. These leukemias are associated with poor prognosis, and novel therapies are desperately needed. To understand the mechanisms underlying AF10-fusion leukemias, Ani Deshpande and colleagues generated animal models of these tumors, and subjected them to transcriptomic, epigenomic, proteomic, and functional genomic analysis. These studies revealed that AF10 fusions activate inflammatory pathways by recruiting an enzyme called JAK kinase. Importantly, inflammatory signaling is critical for tumor growth, and pharmacological inhibitors of JAK kinase exert potent anti-cancer effects in models of AF10-fusion leukemia. These studies identify JAK kinase as a therapeutic target in this aggressive form of cancer.
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Cell 2021 Jan 21 ;184(2):352-369.e23
Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis.
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Cancer Res 2020 Dec 1 ;80(23):5393-5407
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Nat Commun 2021 Jul 5 ;12(1):4130
Neoplastic and immune single cell transcriptomics define subgroup-specific intra-tumoral heterogeneity of childhood medulloblastoma.
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Neuro Oncol 2021 Jun 2 ;
Depletion of kinesin motor KIF20A to target cell fate control suppresses medulloblastoma tumour growth.
Qiu R, Wu J, Gudenas B, Northcott PA, Wechsler-Reya RJ, Lu Q
Commun Biol 2021 May 11 ;4(1):552
Chen BR, Deshpande A, Barbosa K, Kleppe M, Lei X, Yeddula N, Vela PS, Campos AR, Wechsler-Reya RJ, Bagchi A, Meshinchi S, Eaves C, Jeremias I, Haferlach T, Frank DA, Ronai Z, Chanda S, Armstrong SA, Adams PD, Levine RL, Deshpande AJ
Blood 2021 Jun 17 ;137(24):3403-3415
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Cell Stress 2021 Feb 18 ;5(3):37-39
Structure-based virtual screening identifies an 8-hydroxyquinoline as a small molecule GLI1 inhibitor.
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