Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell's cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell's mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.

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Copyright © 2022 Angstadt, Zhu, Jaffee, Robinson and Anders.

Déclaration de conflit d'intérêts

RA reports grants and personal fees from Bristol Myers Squibb, and personal fees from AstraZeneca and Merck SD. DR is currently exploring formation of a startup company. A patent has been granted on the use of 4-HAP to treat disease, and DR is an inventor on this patent. EJ reports grants from Bristol Myers Squibb and Lustgarten, as well as grants from Abmeta and Lustgarten, and personal fees from Genocea, Achilles, DragonFly, CSTONE, Candel Therapeutics, and Parker Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.