Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer cell spread via extracellular signal-regulated kinase 2
Open accessAbstract
It is predicted that pancreatic ductal adenocarcinoma (PDAC) will become the second most lethal cancer in the US by 2030. PDAC includes a fibrous-like stroma, desmoplasia, encompassing most of the tumor mass, which is produced by cancer-associated fibroblasts (CAFs) and includes their cell-derived extracellular matrices (CDMs). Since elimination of desmoplasia has proven detrimental to patients, CDM reprogramming, as opposed to stromal ablation, is therapeutically desirable. Hence, efforts are being made to harness desmoplasia's anti-tumor functions. We conducted biomechanical manipulations, using variations of pathological and physiological substrates in vitro, to culture patient-harvested CAFs and generate CDMs that restrict PDAC growth and spread. We posited that extrinsic modulation of the environment, via substrate rigidity, influences CAF's cell-intrinsic forces affecting CDM production. Substrates used were polyacrylamide gels of physiological (~1.5 kPa) or pathological (~7 kPa) stiffnesses. Results showed that physiological substrates influenced CAFs to generate CDMs similar to normal/control fibroblasts. We found CDMs to be softer than the corresponding underlying substrates, and CDM fiber anisotropy (i.e., alignment) to be biphasic and informed via substrate-imparted morphological CAF aspect ratios. The biphasic nature of CDM fiber anisotropy was mathematically modeled and proposed a correlation between CAF aspect ratios and CDM alignment; regulated by extrinsic and intrinsic forces to conserve minimal free energy. Biomechanical manipulation of CDMs, generated on physiologically soft substrates, leads to reduction in nuclear translocation of pERK1/2 in KRAS mutated pancreatic cells. ERK2 was found essential for CDM-regulated tumor cell spread. In vitro findings correlated with in vivo observations; nuclear pERK1/2 is significantly high in human PDAC samples. The study suggests that altering underlying substrates enable CAFs to remodel CDMs and restrict pancreatic cancer cell spread in an ERK2 dependent manner.
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The αSMA-high, matrix-producing-high state is reversible, supported by the responsiveness of matrix production and the αSMA promoter to extracellular cues including substrate stiffness.
“the responsiveness of matrix production by fibroblasts and the αSMA promoter to a range of extracellular cues, including substrate stiffness, supports the idea that the αSMA-high, matrix producing-high state is reversible63,64,137–139.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [63]
The Results and Conclusions (pages not available in our copy) show that substrate stiffness changes the architecture of matrices produced by pancreatic cancer-associated fibroblasts and that soft substrates can induce tumor-restrictive matrices. They do not report αSMA promoter responsiveness or demonstrate reversal of an αSMA-high, matrix-production-high state; the measured matrix change is chiefly anisotropy, not production level. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPhysical changes in the ECM are capable of activating CAFs.
“Physical changes in the ECM are also capable of activating CAFs53,61–64.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [63]
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Yuan, Z., Li, Y., Zhang, S., Wang, X., Dou, H., Yu, X., Zhang, Z., Yang, S., & Xiao, M. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01744-8 · Cited by 977 · see citing works
The extracellular matrix in tumor progression and metastasis
Eble, J. A., & Niland, S. (2019) · Clinical & Experimental Metastasis · doi:10.1007/s10585-019-09966-1 · Cited by 613 · see citing works
- Authors
- Malik, R., Luong, T., Cao, X., Han, B., Shah, N., Franco-Barraza, J., Han, L., Shenoy, V. B., Lelkes, P. I., & Cukierman, E.
- Affiliations
- Fox Chase Cancer Center (US)
- University of Pennsylvania (US)
- Drexel University (US)
- Temple University (US)
- Corresponding author
- Lelkes, P.I.
- Cukierman, E.
- Venue
- Matrix Biology
- Publisher
- Elsevier BV
- Published
- 2019-08
- Volume
- 81
- Pages
- 50-69
- ISSN
- 0945-053X (ISSN-L)
- PMC
- PMC6504628
- OpenAlex
- W2963431641
- Cited by
- 74
- References
- 80
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 9 · 2023: 9 · 2022: 16 · 2021: 6 · 2020: 14 · 2019: 3
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Matrix Biology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Commonwealth of Pennsylvania
- FCCC
- NIH
- NCI (R01 CA113451, CA006927)
- DOD (W81XH-15-1-0170)
- Martin and Concetta Greenberg Pancreatic Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Keywords
- pancreatic ductal adenocarcinoma, desmoplasia, cancer-associated fibroblasts, extracellular matrix, substrate stiffness, ERK2, KRAS mutation, metastasis, cell aspect ratio, free energy minimization
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Biomechanical Phenomena, Cell Movement, Cell Nucleus, Extracellular Matrix, Humans, Pancreatic Neoplasms, Gene Expression Regulation, Neoplastic, Anisotropy, Coculture Techniques, Mitogen-Activated Protein Kinase 1, Carcinoma, Pancreatic Ductal, NIH 3T3 Cells, Cell Line, Tumor, Cell Proliferation, Mice, Tumor Microenvironment
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