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Pancreatic Cancer Presents Distinct Nanomechanical Properties During Progression

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Abstract

Cancer progression is closely related to changes in the structure and mechanical properties of the tumor microenvironment (TME). In many solid tumors, including pancreatic cancer, the interplay among the different components of the TME leads to a desmoplastic reaction mainly due to collagen overproduction. Desmoplasia is responsible for the stiffening of the tumor, poses a major barrier to effective drug delivery and has been associated with poor prognosis. The understanding of the involved mechanisms in desmoplasia and the identification of nanomechanical and collagen-based properties that characterize the state of a particular tumor can lead to the development of novel diagnostic and prognostic biomarkers. In this study, in vitro experiments were conducted using two human pancreatic cell lines. Morphological and cytoskeleton characteristics, cells’ stiffness and invasive properties were assessed using optical and atomic force microscopy techniques and cell spheroid invasion assay. Subsequently, the two cell lines were used to develop orthotopic pancreatic tumor models. Tissue biopsies were collected at different times of tumor growth for the study of the nanomechanical and collagen-based optical properties of the tissue using Atomic Force Microscopy (AFM) and picrosirius red polarization microscopy, respectively. The results from the in vitro experiments demonstrated that the more invasive cells are softer and present a more elongated shape with more oriented F-actin stress fibers. Furthermore, ex vivo studies of orthotopic tumor biopsies on MIAPaCa-2 and BxPC-3 murine tumor models highlighted that pancreatic cancer presents distinct nanomechanical and collagen-based optical properties relevant to cancer progression. The stiffness spectrums (in terms of Young’s modulus values) showed that the higher elasticity distributions were increasing during cancer progression mainly due desmoplasia (collagen overproduction), while a lower elasticity peak was evident - due to cancer cells softening - on both tumor models. Optical microscopy studies highlighted that collagen content increases while collagen fibers tend to form align patterns. Consequently, during cancer progression nanomechanical and collagen-based optical properties alter in relation to changes in collagen content. Therefore, they have the potential to be used as novel biomarkers for assessing and monitoring tumor progression and treatment outcomes.

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Acknowledgments

This project received funding from the University of Cyprus, Advanced Post-doctoral Research Fellowship (PACAFingerPrints) to A.S. and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement nos. 863955 and 838414) to T.S.

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All procedures performed in the studies were in accordance with ethical standards. all in vivo experiments were conducted in accordance with the animal welfare regulations and guidelines of the Republic of Cyprus and the European Union (European Directive 2010/63/EE and Cyprus Legislation for the protection and welfare of animals, Laws 1994–2013) under a license acquired and approved (No CY/EXP/PR.L2/2018, CY/EXP/PR.L14/2019, CY/EXP/PR.L15/2019) by the Cyprus Veterinary Services committee, the Cyprus national authority for monitoring animal research for all academic institutions.

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  1. Cancer Mechanobiology & Applied Biophysics Group, Basic and Translational Cancer Research Center, School of Sciences, European University Cyprus, 2404, Nicosia, Cyprus

    Andreas Stylianou

  2. European University Cyprus Research Centre Ltd, 2404, Nicosia, Cyprus

    Andreas Stylianou

  3. Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678, Nicosia, Cyprus

    Andreas Stylianou, Chrysovalantis Voutouri, Fotios Mpekris & Triantafyllos Stylianopoulos

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  1. Andreas Stylianou
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Stylianou, A., Voutouri, C., Mpekris, F. et al. Pancreatic Cancer Presents Distinct Nanomechanical Properties During Progression. Ann Biomed Eng 51, 1602–1615 (2023). https://doi.org/10.1007/s10439-023-03168-3

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