David Barry, Ph.D.
The kidney is a common site for metastases arising from malignant cells associated with a variety of primary lesions including the skin, lung, breast, stomach, and pancreas. However, once cancer cells intravasate and enter the blood stream, it is unknown what factors promote specific extravasation at the kidney over other possible metastatic sites. We propose that cooperation between tumor cells in the blood stream and endothelial cells in the kidney vasculature promote such specific targeting. We thus sought to understand tumor-extrinsic mechanisms promoting cancer cell extravasation through the vasculature at characteristic end organs by comparing the transcriptional profiles of endothelial cells associated with the kidney, heart, lung, and liver. Due to extreme functional heterogeneity within the kidney vasculature, we also performed single cell RNA-sequencing to determine transcriptional networks associated with different functional zones in the renal vasculature. Differential expression analysis revealed a variety of kidney-specific transcriptional networks, including several factors specifically expressed in the glomerular endothelial cell population that may have potential to affect transmigration through endothelial cells. We screened candidates by over-expressing candidate genes in HUVEC cells and co-culturing with lung and breast cancer cell lines. The T-Box3 (Tbx3) transcription factor stood out as a protein that promoted a dramatic increase in attachment to the endothelial cell populations when over-expressed. We are currently investigating the regulatory network downstream of Tbx3 that may contribute to increased endothelial cell affinity. Collectively, this study will be the first to reveal a cooperation between metastatic cancer cells and vasculature of the kidney to promote extravasation and metastatic colonization.
Silvana Di Giandomenico, Ph.D.
Chronic anemias are a major medical problem with therapeutic options limited to blood transfusions and erythroid stimulating agents (ESAs). Unfortunately transfusions and ESAs are expensive, time consuming and very often ineffective. New approaches for treating chronic anemias are needed. It takes about 3 weeks for immature hematopoietic stem and progenitor cells to differentiate into red blood cells (RBCs). There is a lot known about the final 3 cell divisions leading to RBCs. Surprisingly little is known about how these terminal stages of erythropoiesis are matched by bone marrow production of more immature erythroid progenitor cells. My project is identifying how production of red blood cell progenitors in the bone marrow is coupled to terminal erythroid maturation. My work promises new therapies for chronic anemias to increase the outflow of immature progenitors with ESAs to support erythroid maturation.
Seaho Kim, Ph.D.
My project seeks to investigate the mechanisms underlying transcriptional activity of the androgen receptor (AR) splice variant AR-v7 which is clinically correlated with poor prognosis in castrate resistant prostate cancer (CRPC) patients.AR signaling is a key driver of prostate cancer (PC) growth and metastatic progression. Thus, androgen deprivation therapy is the first line of treatment for PC. However, most patients develop castration resistant prostate cancer (CRPC), partly due to the expression of transcriptionally active AR splice variants (AR-Vs). AR-v7 is the most prevalent variant expressed in about 60% of CRPC tumors. Currently, there is no therapeutic modality that can inhibit AR-v7 expression or activity and the exact mechanism by which transcription is activated by AR-v7 is unknown. Our preliminary data revealed a unique AR-v7 intranuclear mobility mechanism suggesting that AR-v7 achieves its transcriptional activity despite short residence time on chromatin. Our mechanistic findings could reveal novel therapeutic targets to halt AR-v7 activity in CRPC and improve clinical outcomes.
Geoffrey Markowitz, Ph.D.
My project aims to identify molecular mediators underlying T-cell dysfunction in non-small cell lung cancer (NSCLC),in both the treatment-naïve context and in the context of first-line immunotherapies such as anti-PD-1. T-cells are key agents of the anti-tumor immune response, and enhancing their function through therapies such as anti-PD-1 has been shown to yield significant survival benefits for cancer patients. However, these benefits are temporary, and only effective in a subset of patients. We have globally examined gene expression changes in tumor-infiltrating T-cells both in the presence and absence of anti-PD-1 therapy, and identified a cohort of >100 genes with significantly enhanced expression in the dysfunctional state both in mouse and human samples. We utilize antigen-specific in vitro and in vivo assays to mechanistically dissect the relevance and potency of these dysregulated genes in modulating tumor progression. Ultimately, this work will identify targets for potential future therapeutics, as single agents or in combination with anti-PD-1, to further enhance the anti-tumor immune response and improve outcomes for NSCLC patients.
Maria Zafra Martin, Ph.D.
Kras is the most frequently mutated oncogene, and specific cancer types show a clear bias in the types and frequency of Kras alterations. My proposed project seeks to better understand the impact of the Kras mutational landscape through the generation and analysis of new genetically engineered mouse models. Specifically, my work aims to determine how specific alterations in Kras modulate the tumor microenvironment, how this contributes to the efficacy of immune-based therapies, and ultimately whether Kras mutation profiling could guide treatment decisions. I have developed a series of new conditional Kras mouse models that recapitulate common Kras alterations observed in colorectal (G13D), pancreatic (G12R), and lung cancer (G12C). Our preliminary results show remarkably differences in the early stages of pancreatic cell transformation among all four Kras mutants, associated with dramatic changes in the degree of stromal expansion within the pancreas. We are now exploring how such changes following Kras alterations influence progression to carcinoma, dictate the degree and type of immune cell involvement in these tumors, and mediate the efficacy of immune checkpoint inhibitors.