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The Eischen lab studies multiple proteins, pathways, and non-coding RNA that contribute to tumorigenesis and cancer cell vulnerabilities as well as novel compounds to target these vulnerabilities.

   -Oncogenes (Myc, Mdm2, Mdmx, Mtbp)

   -Apoptosis inhibitors (Bclw, Bcl2, Bclx, Mcl1)

   -Non-coding RNA (miRNA, lncRNA)

   -DNA replication stress mitigators (Smarcal1, Zranb3)

   -Tumor suppressors (p53, Arf)

Cellular Processes/Pathways we study:




   -DNA replication stress

   -DNA damage/repair

   -Genome instability

Discovered BCLW, an anti-apoptotic BCL2 family member that was only thought to be important in sperm development, is a critical survival protein in B cell lymphoma.  BCLW was required for Myc-induced B cell lymphoma development (see A) and the survival of Burkitt lymphoma, as well as being a prognostic indicator for patients with diffuse large B cell lymphoma (see B) (Adams et al.  J. Clinical Investigation, 2017).  Our study was featured by Cancer Discovery, OncLive, and Oncology Times.


We went on to show that BCLW was overexpressed in 6 different types of B cell lymphomas (see C), including some preferentially (Adams and Mitra et al. Clinical Cancer Research, 2017). 


Most recently, we determined that increased BCLW copy number was a mechanism of overexpression in Hodgkin lymphoma (see D).  We also determined that BCLW and BCLX, but not BCL2 or MCL1, were essential for Hodgkin lymphoma survival and targeting them with navitoclax/ABT-263 killed Hodgkin lymphoma cells (see E) (Adams et al. Leukemia, 2020).

We are following up these studies focusing on the role of BCLW in conferring survival advantages to B cell lymphomas.

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Through a computational biology approach, we identified long  non-coding RNA (lncRNA) that regulate epithelial-to-mesenchymal transition in ovarian cancer.  We determined overexpression of one lncRNA, DNM3OS, was associated with worse overall ovarian cancer patient survival.  We verified our results using independent (public and in-house generated) data sets as well as proteo-transcriptomic characterization. Also, biological experiments showed DNM3OS knockdown resulted in altered EMT-linked genes/pathways/proteins, mesenchymal-to-epithelial transition, and reduced ovarian cancer cell migration and invasion (Mitra et al.  Nature Communications, 2017). 

Other projects are focused on identifying core lncRNA that are differentially regulated through pan-cancer analyses.

We were the first to identify that Mdm2 (and then Mdmx) inhibited DNA break repair through a p53-independent mechanism through interaction with Nbs1 of the Mre11/Rad50/Nbs1 DNA break repair complex (Alt et al. J. Bio Chem. 2005; Bouska et al. Mol. Cell. Bio. 2008; Carrillo et al. Oncogene 2015).  We are now working to determine the mechanisms by which Mdm2 and Mdmx inhibit DNA break repair.


We went on to show that combining Mdm2 stabilization pharmacologically with DNA damaging chemotherapy killed ovarian cancer cells (Carrillo et al. Mol. Cancer Research 2015). 

Recently, with mouse models we made the paradigm-shifting discovery that loss of Mdm2 kills lymphoma and sarcoma cells that lack p53 by activating p73 (Feeley et al. Cancer Research 2017). We are testing this concept with an Mdm2 proteolysis targeting chimera (PROTAC) that targets Mdm2 for degradation.


We determined MTBP is a novel transcriptional co-factor of Myc that facilitates Myc transcriptional function and Myc-induced proliferation and cellular transformation (Odvody et al. Oncogene 2010; Grieb et al. Cancer Research 2014).


Loss of Mtbp inhibited Myc-induced B cell lymphoma development and induced apoptosis of triple negative breast cancer ( Grieb et al. Cancer Research 2014; Grieb et al. Mol. Cancer Research 2014).  

We are continuing to investigate Mtbp and the mechanism(s) it uses to regulate Myc and novel ways to target Myc transcriptional function.

We were the first to identify a miRNA (miR-31) that is overexpressed in human lung adenocarcinoma that can independently induce lung cancer in mice. We generated a new lung-specific inducible miR-31 transgenic mouse model. miR-31 induction caused lung hyperplasia and adenoma and then adenocarcinoma. miR-31 also cooperated with mutant KRas, accelerating lung tumorigenesis.  We identified six negative regulators of RAS/MAPK signaling as direct targets of miR-31 (Edmonds et al. J. Clinical Investigation 2016).

Additional studies are ongoing to further characterize miR-31 and other miRNA that contribute to or inhibit lung adenocarcinoma development, survival, or drug sensitivity.

Myc HDAC.jpg

Discovered a novel miRNA-mediated mechanism of Myc-induced apoptosis in normal cells that is inactivated in cancer cells and can be reactivated with HDAC inhibition.  Myc dysregulation transcriptionally upregulates miRNA that target anti-apoptotic Bcl2 family members in normal (non-cancerous) cells, resulting in a reduction in these Bcl2 family members and subsequently death.   In cancer cells, Myc transcriptionally represses these miRNA.  Treatment of cancer cells with HDAC inhibitors converts Myc from a transcriptional repressor to a transcriptional activator at the promoters of these miRNA, leading to the death of the malignant cells.  This Myc transcriptional mechanism was evident in hematopoietic malignancies as well as breast and lung cancers, revealing a "universal truth" about Myc-induced apoptosis (Adams et al. Cancer Res, 2016; Adams et al. Cell Death & Diff, 2016.)

We are using this knowledge to investigate Myc transcriptional regulation and how to target this.  

Genome instability leads to cancer development. Oncogenes and other stimuli (radiation, chemo, etc) cause DNA replication stress, which promotes genome instability. However much remains unknown about the role of DNA replication stress response proteins in cancer development. Using unique mouse models, we are investigating the contributions of two DNA replication stress response proteins (Smarcal1 and Zranb3) in mitigating DNA replication stress in vivo. We determined that loss of Smarcal1 inhibited  gamma irradiation-induced lymphoma development, and increased in vivo sensitivity to the chemotherapeutic drug, 5-fluorouracil  (Puccetti et al. Oncogene 2016). Both were due to increased DNA damage and apoptosis of hematopoietic cells.

In another study, we showed for the first time that Smarcal1 and Zranb3 are both essential, but not redundant, for responding to DNA replication stress and stabilizing replication forks from an in vivo physiologically relevant stress, Myc overexpression. New insights into haploinsufficiency effects of these two proteins were also revealed with an acceleration of lymphoma development in Smarcal1+/- Eu-myc mice and a delay in lymphoma development in Zranb3+/-Eu-myc mice (Puccetti et al Cancer Research 2019).

Additional studies are ongoing to further define the requirements for Smarcal1 and Zranb3 to different DNA replication stresses in vivo.

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