Postdoctoral Training

The postdoctoral training program is designed to provide training in the conduct of scholarly investigation in one of the four scientific areas of expertise of the Cancer Biology Training Grant preceptors. The training is designed for biomedical scientists who have a Ph.D. in basic science (biochemistry, cell biology, genetics, microbiology, immunology, etc.) and for physicians who have basic research experience and interest in the areas studied by the preceptors. Support for postdoctoral trainees is typically for two years. However, all postdoctoral trainees are encouraged to apply for independent postdoctoral funding while they are being supported on the training grant.

Interested postdoctoral fellows currently training in a preceptor's laboratory may apply for support on the Cancer Biology Training Grant when a position becomes available. All positions are selected on a competitive basis by the Cancer Biology Training Grant Steering Committee. Contact the Cancer Biology Training Grant Director for information on how to apply.

If you are interested in postdoctoral training with one of our preceptors, you may contact them directly or direct an inquiry to Carol Lange, PhD at lange047@umn.edu

Current Trainees:

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Julia Austin

austi635@umn.edu
Lange Lab

Breast cancer is a significant health burden. The type of breast cancer is determined by the presence or absence of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor 2 (HER2) gene amplification. Hormone-blocking (anti-estrogens, aromatase inhibitors) therapies in combination with CDK4/6 inhibitors are highly effective for most ER+ cases. In triple negative breast cancer (TNBC), which lacks these receptors, treatment usually involves chemotherapy, which targets proliferating cells, leaving viable quiescent cancer cells. Recent research has uncovered that the glucocorticoid receptor (GR) is involved in breast cancer. In TNBC, GR is associated with chemoresistance and disease recurrence. GR upregulates genes involved in cell migration and invasion. The Lange lab discovered that GR is more cytoplasmic and phosphorylated on Ser134 in TNBC relative to ER+ cases and that pSer134-GR is required for TNBC cell migration. In luminal breast cancer, however, GR is associated with increased survival. Understanding the opposing actions of GR in luminal breast cancer relative to TNBC may provide important clues as to why GR expression is deadly in TNBC. By comparing GR functions in experimental models of both ER+ and TNBC, we aim to discover why GR is protective in ER+ breast cancer, yet oncogenic in TNBC. To discover this, the ligand-activated GR transcriptome in ER+ breast cancer compared to TNBC will be determined. The signaling events that are linked to GR-induced stemness properties in TNBC will also be determined to characterize the oncogenic role of GR in TNBC. This research will identify novel signaling inputs to GR-induced breast cancer stemness properties that could lead to new cancer targets aimed at non-proliferating cells in TNBC.

Megan Ludwig

mlludwig@umn.edu
Drake Lab

Extracellular vesicles (EVs), such as exosomes, are particles that are exported from cells for intercellular communication and contain cargo that can reveal important information about activated signaling networks. We think that proteins, especially phosphoproteins, expressed in EVs may have functional relevance, impacting therapeutic resistance through autocrine or paracrine transfer of critical signaling cargo. Our objective is to understand the composition and function of proteins expressed in EVs and how they contribute to mechanisms of resistance in prostate cancer.

Erica Pratt, PhD

pratte@umn.edu
Parker Lab

Bio coming soon

Kiel Tietz, PhD

tietz025@umn.edu
Dehm Lab

Throughout my career I have always been interested in mechanisms of RNA processing that become dysregulated in disease and cancer. mRNA polyadenylation plays a critical role in stability, translation, and defining the 3’ end of a transcript and our work has identified alternative polyadenylation of the androgen receptor (AR) as a mechanism that is manipulated in metastatic prostate cancer for continued growth. My project focuses on defining the mechanisms that drive alternative polyadenylation of AR in metastatic prostate cancer to determine specific sequence elements and trans-acting factors that can be targeted for more effective treatment of metastatic prostate cancer in patients.

Previous Trainees:

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Ethan Aguilar, PhD

Blazar Lab
eaguilar@umn.edu 

David Burban

Bio coming soon.

Lynsey Fettig, PhD

Yee Lab
fett0050@umn.edu
612-625-2838

Joseph Greene, PhD

Bio coming soon.

Chelsea Lassiter, PhD

Schwertfeger lab
Phone: 612-626-5059
classite@umn.edu

Immunotherapy has shown promise in some solid tumors including breast cancers with high levels of tumor infiltrating lymphocytes (TILs). In other cancers, enhancing T cell infiltration into tumors that lack significant levels of TILs enhances responsiveness to immune based therapies (TILs). TIL infiltration is found in approximately 20% of triple negative breast cancers (TNBCs) and correlates with favorable patient outcome. Therefore, developing approaches to enhance T cell infiltration into primary and metastatic lesions could enhance the percentage of breast cancer patients that respond to immunotherapy.

The signal transducer and activator of transcription (STAT) protein family regulates gene expression changes related to proliferation, apoptosis, and immune response. Constitutively active STAT3 is found in 70% of human solid tumors and regulates immune response to tumor cells.  STAT3 is a potent oncogene and a promising target for immunotherapy. Our lab has shown that a loss of STAT3 leads to an increase in a potent tumor suppressor, STAT1, in multiple cell types. There is also an increase in immunomodulatory genes. In addition, we see a compensatory increase in an immune checkpoint protein, PD-L1, expressed by tumor cells and macrophages

We predict that STAT3 inhibition will enhance T cell infiltration into tumors through increased expression of T cell chemokines, although this will not be sufficient to elicit an anti-tumor response due to increased PD-L1 expression. Therefore, we hypothesize that selectively inhibiting STAT3 and PD-L1 will increase recruitment and enhance activation of T cells at the tumor site, and lead to an effective anti-tumor immune response. 

Kelly Makielski, PhD

Modiano Lab
makie001@umn.edu

Osteosarcoma (OSA) is an uncommon but devastating bone cancer, typically diagnosed in children and adolescents. Despite aggressive treatment, many affected children develop metastatic disease for which there is no effective therapy. Despite advances in cancer therapy, the prognosis with OSA has remained stagnant for over thirty years, highlighting the need for novel treatment strategies. OSA is an immune responsive tumor, making immunotherapy a promising new treatment. One approach to activate the immune system is with oncolytic viruses, such as vesicular stomatitis virus (VSV). Oncolytic viruses selectively replicate in and destroy tumor cells, exposing viral antigens and tumor-associated antigens, triggering an anti-tumor immune response to potentially delay or prevent metastases.

Pediatric OSA research is hindered by its rarity, with fewer than 1,000 new cases diagnosed annually. In contrast, OSA occurs commonly in dogs, and its comparable clinical presentation makes the dog a useful model for translational OSA research. We have previously shown the existence of two molecular OSA phenotypes with distinct biological behavior and prognosis, characterized by both intrinsic tumor properties and host factors. This provides the opportunity to test experimental therapies on two disease phenotypes expected to have different prognoses with standard of care alone.

We are investigating the potential of oncolytic virotherapy with VSV to initiate anti-tumor immunity in canine OSA, with the intent to inform future clinical trials for human patients. Dogs with naturally-occurring OSA will be administered oncolytic VSV in addition to standard of care. We will characterize the anti-tumor immune response induced by VSV, and correlate it with the presence of resident or infiltrating immune cells in the tumor, as well as with clinical endpoints, including time to metastasis and survival time.

We hypothesize that VSV treatment will increase infiltration of immune cells into tumors, generating clonal populations with anti-tumor activity. We anticipate that this immune activation will be associated with improved survival compared to that expected with standard of care alone.Our results will provide valuable information regarding the mechanisms of immune activation by VSV and its potential translation to humans with OSA and other tumors. Determining prognostic factors will help guide treatment decisions, targeting VSV therapy primarily toward patients expected to respond favorably.

Milagros Silva Morales, PhD

Mueller lab
612-625-8614
silva271@umn.edu

Peripheral Immune Self-Tolerance Mechanisms: Anergy, Treg cells and Cancer
Peripheral tolerance is a necessary mechanism to control auto-reactive lymphocytes outside of the thymus. Anergy is a peripheral tolerance mechanism wherein self-reactive lymphocytes become unresponsive after antigen encounter but remain alive. Anergic CD4+ T cells lose their ability to produce growth factors such as IL-2 in response to antigen and develop poor proliferation. Recently, our laboratory reported on an anergic subset of naturally occurring Foxp3CD44hiCD73hiFR4hi polyclonal CD4+ T cells in healthy hosts. Responder CD4+ T cells with this phenotype could also be induced in response to recognition of fetal anti­gens during pregnancy. Interestingly, more than 80% of anergic T cells also specifically expressed the semaphorin receptor Nrp1 by day 18 of pregnancy. Foxp3+ Treg cells are also essential for peripheral immune tolerance and for anergy induction. Remarkably, polyclonal anergic CD4+ T cells can be induced to differentiate into Treg cells when they are adoptively transferred to a lymphopenic host. In particular, Nrp1+ anergic conventional CD4+ T cells displaying a partially de-methylated tTreg-me signature gave rise to functional Foxp3+Nrp1+ pTreg cells with a fully de-methylated Treg-me signature in vivo.

T cell anergy is proposed to be a cellular mechanism of immune evasion contributing to the failure of T cells to eradicate tumors. Tumor antigens can be taken up and presented by APCs in the absence of co-stimulatory signals promoting anergy in antigen-specific CD4+ T cell populations. In addition to anergy, regulatory T cells also have a principal role in promoting immune evasion by cancer cells. Foxp3+ Tregs are specifically recruited to the tumor sites and suppress tumor-specific T cell responses. Their abundant presence is one of the major obstacles to effective antitumor immunotherapy and it is often associated with poor clinical prognosis. In spite of these important discoveries the role of Treg in cancer is controversial. Finally, Nrp1 up-regulation appears to be associated with the tumor invasive behavior and metastatic potential. Increased levels of Nrp1 correlate with tumor aggressiveness, advanced disease stage, and poor prognosis.

Our hypothesis for why Treg cells arise in tumors is that Nrp1+ anergic CD4+ T cells are ideal progenitors for Foxp3+ Treg cells. The objective of my project is to specifically study the role of Nrp1 on the induction of CD4 T cell anergy and the trans-differentiation of anergic conventional T cells into the Foxp3+ Treg cell lineage.