Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications

Abstract

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.

Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study

“… 158 , 159 Furthermore, some PDAC tumors may form after a more prolonged precursor lesion stage, and micrometastasis can occur early on in the tumor development stage. 160 This can be observed as patients often experience local recurrence or metastasis despite a R0 resection; NAT has the potential of eradicating these micrometastases early on prior to surgical resection. 161 NAT was originally introduced for the potential benefits of tumor downstaging prior to surgical resection, but is now more used for identifying patients with favorable tumor biology that will benefit from surgical resection.…”

“…Around 45% of patients do not receive adjuvant chemotherapy as a result of clinical deterioration, postoperative complications and morbidity, or early progression of disease 158,159 . Furthermore, some PDAC tumors may form after a more prolonged precursor lesion stage, and micrometastasis can occur early on in the tumor development stage 160 . This can be observed as patients often experience local recurrence or metastasis despite a R0 resection; NAT has the potential of eradicating these micrometastases early on prior to surgical resection 161 .…”