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Publications of the Week

Inter- and Intra-Tumor Heterogeneity of Metastatic Prostate Cancer Determined by Digital Spatial Gene Expression Profiling

By March 10, 2021March 15th, 2021No Comments

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This week we profile a recent publication in Nature Communications from the laboratory of Dr. Peter Nelson at Fred Hutch. Pictured is Lauren Brady.

Can you provide a brief overview of your lab’s current research focus?

The Nelson lab’s primary research focus is on prostate cancer, the second most common malignancy in men worldwide. The molecular landscape of prostate cancer is complex, and our lab works to identify and understand the underlying drivers which may inform treatment strategies for patients living with this disease. Further, we aim to elucidate the role of the tumor microenvironment in therapeutic resistance and develop a comprehensive understanding of disease progression.

What is the significance of the findings in this publication?

Tumor heterogeneity is a well-known attribute of cancer, including prostate cancer. Inter-individual heterogeneity underlies the concept of precision oncology, but intra-tumor heterogeneity has the potential to contribute to treatment resistance. In this study, we focused on evaluating inter-and intra-tumor heterogeneity of metastatic castration resistant prostate cancer (mCRPC) by utilizing NanoString’s GeoMx digital spatial profiling technology. The data generated allow for further insight into intra-tumoral heterogeneity in advanced disease.

Many of the samples profiled demonstrated high intra-patient homogeneity of mCRPC phenotypes between spatially distinct sites of metastases. However, intra-tumoral heterogeneity was identified in several samples with the presence of divergent phenotypes. These findings have implications for therapy resistance in mCRPC. Further, our study determined an overall low presence of immune cells within different phenotypes of mCRPC. Although expression of some immune checkpoint molecules (e.g. PD1 and PD-L1) was low across samples profiled, high expression of immune checkpoint molecules B7-H3 and TIM-3 was observed paving the way for future investigation into the potential of these markers as therapeutic targets.

The project was a collaborative effort between colleagues at Fred Hutchinson Cancer Research Center, the University of Washington, VAPSHCS-GRECC, and NanoString technologies.

What are the next steps for this research?

Our next steps are to focus on interactions between the tumor cells and cells of the microenvironment – particularly immune cells and chemokines/cytokines. Our original study focused on spatial profiling within tumors. We are now expanding the spatial profiling efforts to include detailed assessments of peri-tumoral and regions of host environments more distant from the tumor cells. Additionally, we are interested in further investigating the immune composition of different phenotypes and genotypes of mCRPC and the implications this may have in personalizing treatment and providing insights into disease progression and therapy resistance.

This work was funded by:

Research support for this study included Cancer Center Support Grant P30CA015704-40, NIH awards P50CA97186, R01CA234715, P01CA163227, U54 CA224079, R50CA221836, and S10OD028685, CDMRP Awards W81XWH-18-1-0406, W81XWH-18-1-0347, and W81XWH-18-1-0354, the Prostate Cancer Foundation, the Institute for Prostate Cancer Research, Veterans Affairs Research Service (SRP), and the Department of Defense, Prostate Cancer Biorepository Network (W81XWH-14-2-0183).

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