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Deciphering cellular plasticity in pancreatic cancer for effective treatments

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Abstract

Cellular plasticity and therapy resistance are critical features of pancreatic cancer, a highly aggressive and fatal disease. The pancreas, a vital organ that produces digestive enzymes and hormones, is often affected by two main types of cancer: the pre-dominant ductal adenocarcinoma and the less common neuroendocrine tumors. These cancers are difficult to treat due to their complex biology characterized by cellular plasticity leading to therapy resistance. Cellular plasticity refers to the capability of cancer cells to change and adapt to different microenvironments within the body which includes acinar-ductal metaplasia, epithelial to mesenchymal/epigenetic/metabolic plasticity, as well as stemness. This plasticity allows heterogeneity of cancer cells, metastasis, and evasion of host’s immune system and develops resistance to radiation, chemotherapy, and targeted therapy. To overcome this resistance, extensive research is ongoing exploring the intrinsic and extrinsic factors through cellular reprogramming, chemosensitization, targeting metabolic, key survival pathways, etc. In this review, we discussed the mechanisms of cellular plasticity involving cellular adaptation and tumor microenvironment and provided a comprehensive understanding of its role in therapy resistance and ways to overcome it.

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Funding

Work in the lab of Azmi AS is supported by R01CA24060701A1 and R37CA215427.

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Authors and Affiliations

  1. Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, HWCRC 740, Detroit, MI, 48201, USA

    Md. Hafiz Uddin, Philip A. Philip & Asfar S. Azmi

  2. Department of Natural Sciences, Lawrence Technological University, 21000 W 10 Mile Rd, Southfield, MI, 48075, USA

    Dingqiang Zhang & Irfana Muqbil

  3. Division of Hematology and Oncology, Department of Medicine, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, 35233, USA

    Bassel F. El-Rayes

  4. Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Herbert Chen

  5. Henry Ford Health Systems, Detroit, MI, 48202, USA

    Philip A. Philip

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  1. Md. Hafiz Uddin
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  5. Herbert Chen
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  6. Philip A. Philip
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  7. Asfar S. Azmi
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Contributions

MHU and DZ wrote the main manuscript text, and MHU prepared Figs. 1, 2, 3, and 4. All authors reviewed the manuscript.

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Correspondence to Md. Hafiz Uddin or Asfar S. Azmi.

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ASA received funding from Colorado Chromatography and Blackstone Therapeutics. ASA serves as a consultant for GLG and Guidepoint.

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Uddin, M.H., Zhang, D., Muqbil, I. et al. Deciphering cellular plasticity in pancreatic cancer for effective treatments. Cancer Metastasis Rev 43, 393–408 (2024). https://doi.org/10.1007/s10555-023-10164-5

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