You may have heard the saying ‘cancer is not one disease, but many diseases,’ referring to the fact that different cancers—even from the same tissue of origin—can be radically different from one another. A new study from the Haffner Lab in the Human Biology Division at Fred Hutch makes this point to a striking degree. Dr. Michael Haffner, a pathologist who has made his career studying prostate cancer, is clear-eyed in his goals to take on this tenacious disease. “We’ve learned very important things from studying various models of prostate cancer over the years, but there are two important goals for the field to strive for in its ongoing efforts to treat this disease: first, we need to be studying prostate cancer in human patients (its ‘natural habitat,’ so to speak), and second, we really need to understand metastatic prostate cancer—it’s this aggressive form of the disease which often kills patients.”
To achieve these goals, Haffner and colleagues at Fred Hutch are taking advantage of an innovative program called the University of Washington Prostate Cancer Rapid Autopsy Program. Haffner explains, “As part of this program, patients who succumb to prostate cancer allow us to sample their tumor tissue soon after death—this gives us critical access to the full breadth of tumor biology (up to tens of discrete primary and metastatic tumors in a single patient) preserved as close to their original state as possible. It’s a translational research tool that very few laboratories are lucky enough to have, and it unlocks the possibility to study tumor heterogeneity to a degree not possible before.”
In a recent publication in the Journal of Clinical Investigation, a team of Fred Hutch scientists led by Haffner profiled hundreds of samples from dozens of metastatic prostate cancer (mPC) patients who participated in the Rapid Autopsy Program. By quantifying the expression of a panel of well-known prostate cancer marker genes, the team was able to categorize different tumor samples into molecular subtypes. Examining the distribution of these subtypes revealed a dazzling diversity—between patients, and even within the same patient. When they tabulated subtypes in each patient, the team was surprised to find that only a minority (<30%) of patients had what they described as ‘homogeneous’ disease—consisting predominantly of a single PC subtype. Instead, patients often showed combinations of two or more subtypes, with some showing considerable subtype diversity across metastatic sites.
Do these different molecular subtypes lead to different cancer cell behaviors? To this end, the team measured a genetic marker of cellular proliferation, Ki-67, in their samples. Here again, they found that these tumors follow no hard-and-fast rules—even within the same patient, different metastases can show large differences in proliferative index, part of which is associated with specific subtypes, but part of which is also subtype-independent. “This is really quite striking,” notes Haffner, “that sometimes in the same patient, you can have two metastases that—despite having very similar genetic alterations—show altogether different behaviors.”
So, prostate cancer tumors vary—but does this heterogeneity have clinical implications? While the team’s statistical analyses were challenged with a relatively small sample size, they noted several trends between the degree of heterogeneity and various clinical metrics in patients. Among these was a counterintuitive trend indicating that patients with less heterogeneity demonstrated less time between the first detected bone metastasis and death (i.e. more severe disease).
Overall, this study stands as one of the largest-scale efforts to profile the heterogeneity of metastatic prostate cancer to date; it also demonstrates that understanding prostate cancer will require understanding an entire molecular ecosystem, even within a single patient. As Haffner notes, “We’re very grateful both to the patients who have so graciously donated their tissue to this effort and to the village that it takes to make programs like this a success—this study is part of an ongoing effort to better understand this disease as we progress from treatments to cures, and it already gives us many interesting hypotheses to follow up on.”
The spotlighted work was funded by the National Institutes of Health, the U.S. Department of Defense Prostate Cancer Research Program, the Doris Duke Charitable Foundation, the V Foundation, the Prostate Cancer Foundation, the Safeway Foundation, the Richard M. Lucas Foundation, the Institute of Health Carlos III, the Fred Hutch/UW Cancer Consortium, a Burroughs Wellcome Fund Career Award, the Brotman Baty Institute for Precision Medicine, and the UW/FHCC Institute for Prostate Cancer Research.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Michael Haffner, Peter Nelson, Colm Morrissey, Gavin Ha, Michael Schweizer, Eva Corey, Daniel Lin, Robert B. Montgomery, Evan Yu, and Heather Cheng contributed to this research.
Roudier, M. P., Gulati, R., Sayar, E., Patel, R. A., Tratt, M., Richards, H. M., Cejas, P., Munoz Gomez, M., Qiu, X., Xie, Y., Hanratty, B., Zaidi, S., Zhao, J. L., Adil, M., Mittal, C., Zhao, Y., Dumpit, R., Coleman, I., Low, J.-Y., … Haffner, M. C. (2025). Patterns of intra- and inter-tumor phenotypic heterogeneity in lethal prostate cancer. Journal of Clinical Investigation.
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.
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