The cancer cell’s control center
Cancers depend on dysregulation of many normal cell processes. These processes are often controlled by the cell nucleus, specifically by the DNA sequence (genome) and its regulation (epigenome).
Dysregulation of nuclear processes encoded within the genome and/or epigenome drive many of the detrimental properties of cancer cells, including defective DNA repair and mutation accumulation, altered inflammatory signaling and immune regulation, unrestrained cell growth and survival, tissue invasion and metastasis, and drug resistance. An understanding of these processes—including their dysregulation in aging and differences between races and ethnicities—can lead to new approaches for patient- and population-specific risk assessment, early detection and diagnosis of cancer, as well as novel therapeutic interventions.
Directors' statement
The Cancer Genome and Epigenetics Program brings together experts in nuclear dysfunction in cancer. Analysis of the genome and epigenome is inherently computationally intensive, and our program also includes experts in computational biology. The range of research areas among our faculty members—along with our shared interests in how nuclear dysregulation drives cancer growth—fosters strong interactions that lead to breakthrough discoveries; and consequently, treatments for cancers of the blood, brain, breast and pancreas.
– Peter Adams, Ph.D., Program Director
Scientific highlights
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.
Publications
FBXO44 promotes DNA replication-coupled repetitive element silencing in cancer cells.
Shen JZ, Qiu Z, Wu Q, Finlay D, Garcia G, Sun D, Rantala J, Barshop W, Hope JL, Gimple RC, Sangfelt O, Bradley LM, Wohlschlegel J, Rich JN, Spruck C
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.
Tiwari A, Tashiro K, Dixit A, Soni A, Vogel K, Hall B, Shafqat I, Slaughter J, Param N, Le A, Saunders E, Paithane U, Garcia G, Campos AR, Zettervall J, Carlson M, Starr TK, Marahrens Y, Deshpande AJ, Commisso C, Provenzano PP, Bagchi A
Gastroenterology 2020 Nov ;159(5):1882-1897.e5
Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma.
Rusert JM, Juarez EF, Brabetz S, Jensen J, Garancher A, Chau LQ, Tacheva-Grigorova SK, Wahab S, Udaka YT, Finlay D, Seker-Cin H, Reardon B, Gröbner S, Serrano J, Ecker J, Qi L, Kogiso M, Du Y, Baxter PA, Henderson JJ, Berens ME, Vuori K, Milde T, Cho YJ, Li XN, Olson JM, Reyes I, Snuderl M, Wong TC, Dimmock DP, Nahas SA, Malicki D, Crawford JR, Levy ML, Van Allen EM, Pfister SM, Tamayo P, Kool M, Mesirov JP, Wechsler-Reya RJ
Cancer Res 2020 Dec 1 ;80(23):5393-5407
Biomedical applications of nanomaterials in the advancement of nucleic acid therapy: Mechanistic challenges, delivery strategies, and therapeutic applications.
Yadav K, Sahu KK, Sucheta, Gnanakani SPE, Sure P, Vijayalakshmi R, Sundar VD, Sharma V, Antil R, Jha M, Minz S, Bagchi A, Pradhan M
Int J Biol Macromol 2023 Apr 26 ;241:124582
3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.
Okonechnikov K, Camgöz A, Chapman O, Wani S, Park DE, Hübner JM, Chakraborty A, Pagadala M, Bump R, Chandran S, Kraft K, Acuna-Hidalgo R, Reid D, Sikkink K, Mauermann M, Juarez EF, Jenseit A, Robinson JT, Pajtler KW, Milde T, Jäger N, Fiesel P, Morgan L, Sridhar S, Coufal NG, Levy M, Malicki D, Hobbs C, Kingsmore S, Nahas S, Snuderl M, Crawford J, Wechsler-Reya RJ, Davidson TB, Cotter J, Michaiel G, Fleischhack G, Mundlos S, Schmitt A, Carter H, Michealraj KA, Kumar SA, Taylor MD, Rich J, Buchholz F, Mesirov JP, Pfister SM, Ay F, Dixon JR, Kool M, Chavez L
Nat Commun 2023 Apr 21 ;14(1):2300
The DOT1L-MLLT10 complex regulates male fertility and promotes histone removal during spermiogenesis.
Lin H, Cossu IG, Leu NA, Deshpande AJ, Bernt KM, Luo M, Wang PJ
Development 2023 Apr 21 ;
Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells.
Missinato MA, Murphy S, Lynott M, Yu MS, Kervadec A, Chang YL, Kannan S, Loreti M, Lee C, Amatya P, Tanaka H, Huang CT, Puri PL, Kwon C, Adams PD, Qian L, Sacco A, Andersen P, Colas AR
Nat Commun 2023 Mar 27 ;14(1):1709
Shining light on reprogramming Tregs for cancer therapy.
Wang ES, Gray NS
Cell Chem Biol 2023 Mar 16 ;30(3):231-233
Gliosarcoma with extensive extracranial metastatic spread and familial coincidence: A case report.
Friker LL, Tzaridis T, Enkirch SJ, Lüders C, Hattingen E, Kristiansen G, Goschzik T, Waha A, Lütter C, Weller J, Herrlinger U, Pietsch T, Gessi M, Baumert BG, Gielen GH
Pathol Res Pract 2023 Apr ;244:154399
