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.
Director's statement
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.
– 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
Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios.
Verano AL, You I, Donovan KA, Mageed N, Yue H, Nowak RP, Fischer ES, Wang ES, Gray NS
ACS Chem Biol 2022 Aug 25 ;
Subgroup-Enriched Pathways and Kinase Signatures in Medulloblastoma Patient-Derived Xenografts.
Leskoske KL, Garcia-Mansfield K, Sharma R, Krishnan A, Rusert JM, Mesirov JP, Wechsler-Reya RJ, Pirrotte P
J Proteome Res 2022 Sep 2 ;21(9):2124-2136
The Role of DOT1L in Normal and Malignant Hematopoiesis.
Arnold O, Barbosa K, Deshpande AJ, Zhu N
Front Cell Dev Biol 2022 ;10:917125
Coming in from the cold: overcoming the hostile immune microenvironment of medulloblastoma.
Eisemann T, Wechsler-Reya RJ
Genes Dev 2022 May 1 ;36(9-10):514-532
PDGF signaling inhibits mitophagy in glioblastoma stem cells through N6-methyladenosine.
Lv D, Gimple RC, Zhong C, Wu Q, Yang K, Prager BC, Godugu B, Qiu Z, Zhao L, Zhang G, Dixit D, Lee D, Shen JZ, Li X, Xie Q, Wang X, Agnihotri S, Rich JN
Dev Cell 2022 Jun 20 ;57(12):1466-1481.e6
Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.
Li Q, Han Z, Singh N, Terré B, Fame RM, Arif U, Page TD, Zahran T, Abdeltawab A, Huang Y, Cao P, Wang J, Lu H, Lidov HGW, Surendran K, Wu L, Virga JQ, Zhao YT, Schüller U, Wechsler-Reya RJ, Lehtinen MK, Roy S, Liu Z, Stracker TH, Zhao H
Cell Death Differ 2022 Aug ;29(8):1596-1610