Targeted cancer therapies are an expanding field of effective therapeutic approaches. While previous chemotherapy agents indiscriminately killed rapidly proliferating cells, newer “precision medicine” approaches attempt to target specific differences between tumor and normal cells. In a nutshell, targeted therapies are those that “require expression of the target antigen on cancer cells (to ensure tumor reduction/elimination),” stated researchers at the Fred Hutchinson Cancer Center and collaborating institutes. Dr. Michael Haffner, an Assistant Professor in the Human Biology and Clinical Research Divisions, studies tumor heterogeneity—the concept that cells forming a tumor differ from each other on many levels including different proteins which they present on their surfaces. Tumor heterogeneity is increasingly recognized as a contributing factor to drug resistance. Dr. Haffner and his colleagues wanted to better understand the tumor heterogeneity and cell surface marker landscape in prostate cancer, the second most common cancer in the U.S. From their analysis of patient samples and animal models of prostate cancer, the researchers discovered that surface proteins on two types of advanced or castrate-resistant prostate cancers have more heterogeneity than previously thought and importantly, key therapeutic targets are among those not consistently expressed on each cell in a single tumor. Instead, the researchers identified other tumor signatures that might provide targets with broad acting therapeutic effects for these castrate-resistant prostate cancers. Their findings were published in PNAS.
Cancer resistance to a targeted therapy takes two major forms: the first is conventional resistance where a drug’s target mutates so the drug can no longer inhibit the oncogenic—cancer causing—function of the protein. The second form of resistance, lineage plasticity, is a bit more nuanced. These tumor cells adapt through various ways to overcome cell stress including stress induced by a therapeutic agent but also environmental stress of tumor invasion and metastasis. This latter form of resistance can stem from tumor heterogeneity that allows for some tumor cells to overcome certain stresses and maintain tumor growth despite stressful conditions. Studies have shown that castrate-resistant prostate cancers have some level of cell surface marker tumor heterogeneity, but to better define each cell lineage within a tumor, a deeper look was needed.
“To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples,” explained the researchers. Their previous work with a smaller set of castrate-resistance prostate cancer biopsies identified JAK-STAT and FGFR signaling pathways as essential for plasticity. The STAT family of proteins are transcription factors that activate expression of specific genes involved in numerous cellular processes. “Reasoning that lineage plasticity is likely driven by transcription factor (TF) networks, we focused on shared and unique gene-regulatory networks (GRNs) across samples,” shared the researchers. From their extensive investigation of multiple sample types, the researchers were able to characterize several new linages in castrate-resistant prostate cancers, including GRNs that were specific to either adenocarcinomas or neuroendocrine prostate cancers. “Our findings provide a comprehensive atlas of progressive heterogeneity in late-stage prostate cancer,” concluded the researchers. In the future, this atlas of GRNs may be used as a tool to classify prostate cancers to better personalize therapy plans for patients. Importantly, “this study is a highly collaborative effort that included investigators at The Memorial Sloan Kettering Cancer Center, the University of Washington and Fred Hutch,” commended Dr. Haffner. “The project brought together highly unique biospecimens and technical and analytical expertise across the different institutions.”
The spotlighted research was funded by the National Institutes of Health, the Institute for Prostate Cancer Research, the Prostate Cancer Foundation, the Burroughs Wellcome Fund, the National Research Foundation of Korea, the Department of Defense, the Doris Duke Charitable Foundation, the V Foundation, and the Starr Cancer Consortium.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Lawrence True, Peter Nelson, and Michael Haffner contributed to this work.
Zaidi S, Park J, Chan JM, Roudier MP, Zhao JL, Gopalan A, Wadosky KM, Patel RA, Sayar E, Karthaus WR, Kates DH, Chaudhary O, Xu T, Masilionis I, Mazutis L, Chaligné R, Obradovic A, Linkov I, Barlas A, Jungbluth AA, Rekhtman N, Silber J, Manova-Todorova K, Watson PA, True LD, Morrissey C, Scher HI, Rathkopf DE, Morris MJ, Goodrich DW, Choi J, Nelson PS, Haffner MC, Sawyers CL. 2024. Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen-targeted therapies. Proc Natl Acad Sci USA. 121(28):e2322203121.
Science spotlight writer Annabel Olson is a postdoctoral research fellow in the Nabet lab at Fred Hutchinson Cancer Center. Her research focuses on studying the mechanisms that drive cancer development for both genetic and virus-associated cancers. A key tool in her research is the use of targeted protein degradation to dissect dysregulated signaling pathways in cancer and to double as a relevant pre-clinical therapeutic platform.
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