Prostate cancer associated fibroblasts have distinct morphomechanical features that are associated with patient outcome
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Abstract
Tumour development and progression reshape the physical properties of the surrounding tumour microenvironment (TME) including its biomechanical traits. This is driven by a prominent cell type in the TME, cancer associated fibroblasts (CAFs), which increases tissue stiffness via extracellular matrix deposition and remodelling. Currently, it is unclear whether there are also physical changes to CAFs at the cellular level and, if so, how they relate to patient outcome. Here we show that CAFs have distinct morphological and biomechanical features from normal fibroblasts. We examined matched, patient-derived CAFs and non-malignant prostate fibroblasts (NPFs) from 35 patients with primary prostate cancer. Morphologically, CAFs had more aligned stress fibres, and larger and more elongated nuclei, based on quantitative image analysis of confocal microscopy images. In addition, single-cell mechanical measurements using real-time deformability cytometry showed that CAFs are larger and stiffer than NPFs. These changes were consistent across patients and validated with atomic force microscopy. A combined morphomechanical score encompassing these features was significantly associated with patient outcome. In transcriptomic analyses, the score was correlated with microtubule dynamics and a myofibroblast phenotype. Importantly, we also demonstrated that morphomechanical features of prostate fibroblasts are modified by approved treatments for prostate cancer, such as docetaxel, and other small molecular inhibitors, such as axitinib. In summary, changes in cellular morphomechanical properties are a consistent feature of CAFs and associated with patient outcome. Moreover, cellular morphomechanical properties can be therapeutically targeted, potentially providing a new strategy for manipulating the TME to control cancer progression.
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Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation & Life Science Editors Potential Conflicts of Interest: None
PUNCHLINE Prostate cancer–associated fibroblasts (CAFs) exhibit conserved and quantifiable differences in morphology and biomechanics compared to matched non-malignant fibroblasts (NPFs). These morphomechanical features—particularly increased stiffness, volume, and nuclear elongation—are correlated with transcriptional programs and clinical outcomes, positioning fibroblast biophysics as a potential biomarker and therapeutic target in prostate cancer.
BACKGROUND Tumor progression is tightly intertwined with the tumor microenvironment (TME), where CAFs play a key role by remodeling the extracellular matrix and altering tissue mechanics. While bulk tissue …
Review coordinated by Life Science Editors Foundation Reviewed by: Dr. Angela Andersen, Life Science Editors Foundation & Life Science Editors Potential Conflicts of Interest: None
PUNCHLINE Prostate cancer–associated fibroblasts (CAFs) exhibit conserved and quantifiable differences in morphology and biomechanics compared to matched non-malignant fibroblasts (NPFs). These morphomechanical features—particularly increased stiffness, volume, and nuclear elongation—are correlated with transcriptional programs and clinical outcomes, positioning fibroblast biophysics as a potential biomarker and therapeutic target in prostate cancer.
BACKGROUND Tumor progression is tightly intertwined with the tumor microenvironment (TME), where CAFs play a key role by remodeling the extracellular matrix and altering tissue mechanics. While bulk tissue stiffness has been studied extensively in cancer, the mechanical properties of individual CAFs—and their consistency across patients and link to clinical outcomes—are not well defined. The study leverages a rare resource: 35 pairs of matched CAF and NPF primary cultures from radical prostatectomy specimens, enabling a systematic comparison of morphomechanical traits and their clinical relevance.
QUESTIONS ADDRESSED Do prostate CAFs exhibit consistent morphomechanical changes compared to matched NPFs?
Are these features linked to patient outcomes or tumor grade?
Can CAF biomechanics be modulated by signaling pathways or therapeutic agents?
Do these traits reflect distinct transcriptional signatures, particularly the myofibroblast-like (myCAF) phenotype?
SUMMARY Using real-time deformability cytometry (RT-DC), atomic force microscopy (AFM), and high-content imaging, the authors show that CAFs are consistently stiffer, larger, and more elongated than NPFs across patients. A principal component–derived morphomechanical score integrates five features (volume, Young’s modulus, nuclear area, nuclear circularity, and F-actin alignment) and stratifies patients by clinical outcome. Transcriptomic correlates reveal a link to microtubule dynamics and myCAF signatures. Notably, CAF stiffness can be altered by TGF-β signaling and anti-cancer agents, suggesting potential avenues for stromal reprogramming.
KEY RESULTS CAFs Exhibit Conserved Biophysical Phenotypes
Across 35 matched pairs, CAFs are consistently stiffer (RT-DC, AFM) and larger in both nuclear and cytoplasmic dimensions.
F-actin fibers in CAFs are more aligned, and nuclei more elongated, than in NPFs.
These features were independent of tumor grade but associated with clinical relapse.
A Composite Morphomechanical Score Correlates with Outcome
PCA of the five morphomechanical traits yields a score that stratifies patients.
Higher scores are associated with biochemical and clinical relapse.
Transcriptional Correlates of Biomechanical States
49 genes correlate with the morphomechanical score; top hits include NAV3, MYOCD, and ARHGAP28, implicating cytoskeletal remodeling.
Enrichment for microtubule and myCAF signatures supports a contractile phenotype underlying mechanical changes.
Biophysical Traits Are Pharmacologically Modifiable
TGF-β1 increases nuclear size and stiffness in CAFs, while TGF-β inhibition reduces stiffness.
Docetaxel and axitinib also modulate fibroblast biophysics, suggesting that approved cancer therapies may influence the stromal compartment.
STRENGTHS Large, well-annotated cohort with matched CAF/NPF pairs.
Rigorous integration of imaging, biophysical assays, and transcriptomics.
Clear demonstration of phenotypic consistency and clinical relevance.
Insight into mechanobiological regulation and therapeutic modulation of CAFs.
FUTURE WORK Can morphomechanical profiling be applied to in situ biopsies or circulating fibroblasts?
Is the morphomechanical phenotype of CAFs reversible, and does this influence tumor behavior?
How do CAF mechanics interface with epithelial cell signaling and immune exclusion?
Could targeted reprogramming of CAFs (e.g., via TGF-β blockade) improve therapeutic response?
FINAL TAKEAWAY This study establishes that prostate CAFs are not only functionally distinct but also physically distinct in measurable and clinically relevant ways. The morphomechanical phenotype of CAFs emerges as a novel dimension of tumor biology—potentially serving as both a biomarker and a therapeutic target. By placing CAF biomechanics in the context of differentiation state, gene expression, and treatment response, the work opens new avenues for integrating stromal biology into precision oncology.
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