A world-first cellular atlas reveals supposedly normal prostate cells can already carry cancer-linked mutations, opening new possibilities for early detection.
A world-first cellular atlas of early-stage prostate cancer has revealed that many prostate cells appearing normal under the microscope already carry cancer-associated molecular changes, raising the prospect of earlier and more precise detection strategies for the disease.
Published in the American Association for Cancer Research journal Cancer Research, the study used single-cell and spatial transcriptomic profiling to map the cellular architecture of early prostate tumours in unprecedented detail.
Researchers from the Garvan Institute of Medical Research analysed tissue samples from 24 patients with early-stage prostate cancer, drawing on material from the Garvan St Vincent’s Prostate Cancer Biobank.
Using single-cell RNA sequencing and spatial transcriptomics, the team catalogued 11 major cell types, 50 minor subtypes and multiple distinct cellular states within tumour tissue.
The findings suggest prostate carcinogenesis may begin years before conventional histopathology can identify overt malignant transformation.
“We’ve captured a molecular readout showing years of cancer development,” said Professor Alexander Swarbrick, co-director of the Cancer Ecosystems Program at Garvan.
“What’s particularly surprising is the significant number of cells that look perfectly ordinary but have already acquired DNA changes associated with cancer.
“This suggests that current diagnostic methods using conventional microscopy may not be granular enough to detect these early mutations.”
The researchers found epithelial cells in histologically normal tissue frequently harboured early genomic alterations linked to malignancy.
The findings challenge reliance on morphology alone for prostate cancer diagnosis and risk stratification and point towards future molecular screening approaches capable of detecting pre-malignant cellular states before visible pathological changes emerge.
The researchers said their work may ultimately help distinguish indolent disease from tumours likely to progress aggressively.
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Clinical lead Professor Anthony Joshua, head of the Department of Medical Oncology at St Vincent’s Hospital Sydney, said understanding the earliest stages of tumour evolution was critical to improving predictive testing and treatment selection.
“Currently we don’t know how prostate cancer starts. Understanding the sequence of events that lead to life-threatening disease – and finding the signatures of cancer in normal-looking cells – is essential for creating better predictive tests and therapies,” he said.
“While most prostate cancer patients respond well to current treatments, this atlas provides foundational knowledge of the disease’s first stages that could help us pinpoint those at high risk of dangerous progression, who need more intensive intervention.”
Among the study’s most notable discoveries was the identification of a previously undescribed stromal cell population termed perineural cancer-associated fibroblasts.
These fibroblasts were located adjacent to nerves within tumours and appeared to possess specialised signalling pathways for neural interaction.
The finding may be clinically significant given the longstanding association between perineural invasion and poorer prostate cancer outcomes.
The researchers said the cells could contribute to tumour growth, nerve recruitment or metastatic spread along neural pathways.
They plan to expand the cohort and further investigate the apparently normal cells carrying genomic abnormalities, alongside functional studies of the newly identified fibroblast subtype.
“We’ve had a peek through the window, but it’s still somewhat blurry,” said Professor Swarbrick.
“Now we have more precise questions about these pre-malignant cells, and we can apply more focused techniques to be crystal clear about the sequence of genetic events that drive this cancer.”
Prostate cancer remains Australia’s most commonly diagnosed cancer in men, affecting around one in five during their lifetime.
