New Avenues in Pancreatic Cancer Research: Targeting Amoeboid Behavior and the Tumor Microenvironment for Improved Therapies

Pancreatic ductal adenocarcinoma (PDAC), often referred to as pancreatic cancer, continues to be one of the most challenging and deadly cancers, with a bleak prognosis. The five-year survival rate remains staggeringly low at around 7%, making it a formidable adversary in the world of oncology. It’s estimated that by 2030, PDAC could become the second leading cause of cancer-related deaths, underscoring the urgent need for innovative strategies to tackle this aggressive malignancy. One of the key factors contributing to the dismal survival rates in PDAC is its propensity to metastasize. More than 50% of patients are diagnosed at an advanced stage where the cancer has already spread to distant organs. Metastasis, the process by which cancer cells disseminate and establish secondary tumors in distant sites, is the primary driver of cancer-related deaths. To improve the prospects for patients battling PDAC, it’s crucial to gain a deeper understanding of the biology of metastasis, particularly how cancer cells interact with their microenvironment and the different strategies they employ to disseminate.

Cancer cells can employ various strategies to facilitate their migration, and recent research has shed light on a less explored migration mode known as “amoeboid behavior.” This phenomenon involves the cancer cells adopting a rounded morphology and utilizing a unique set of mechanisms for movement. Amoeboid behavior is influenced by the tumor microenvironment, and it comes into play when cancer cells need to navigate through three-dimensional matrices or tight spaces. In the context of pancreatic cancer, where the tumor microenvironment is characterized by a dense extracellular matrix, amoeboid behavior appears to be a noteworthy feature. This behavior is associated with high activity of specific molecular players, including RhoA, RhoC, and ROCK (Rho-associated protein kinase), which are key regulators of cellular processes involved in metastasis. Pancreatic tumors create a microenvironment that not only supports amoeboid behavior but also promotes cancer stemness and chemoresistance—two markers of aggressiveness that make PDAC notoriously hard to treat.

Cancer metastasis often involves a complex dance of genetic and molecular events within the tumor cells. Epithelial-to-mesenchymal transition (EMT) is one such process that plays a significant role in increasing a cancer cell’s ability to migrate and invade. During EMT, cancer cells undergo a transformation, losing their epithelial characteristics while gaining mesenchymal traits, making them more invasive. Interestingly, research indicates that amoeboid behavior is not mutually exclusive from EMT; in fact, there is a partial overlap in the genetic and molecular characteristics of amoeboid and mesenchymal cancer cells. In a surprising discovery, amoeboid cells in PDAC displayed some of the EMT markers. The existence of amoeboid cells with a partial EMT signature challenges our previous understanding of PDAC’s migration behavior, particularly in a three-dimensional context. Furthermore, amoeboid cells were observed to be more migratory than their mesenchymal counterparts in a two-dimensional environment. This plasticity in cell behavior, where mesenchymal cells can shift towards an amoeboid state and vice versa, adds an extra layer of complexity to the metastatic process. While the exact mechanisms driving this interconversion are not yet fully understood, it opens up intriguing possibilities for targeted interventions aimed at disrupting the plasticity of cancer cells and their migratory strategies.

The true test of any scientific discovery is its relevance in the clinical setting, and the presence of amoeboid cells is not just a laboratory phenomenon. Evidence of amoeboid behavior exists within actual patient tissues. Tissue samples from PDAC patients reveal the presence of rounded-amoeboid cells within tumors, often in the peripheral regions. Additionally, studies on orthotopic models of PDAC, where human cancer cells are implanted into the pancreas of mice, show a similar coexistence of amoeboid and mesenchymal cells. These findings mirror the genetic and molecular features observed in laboratory settings, highlighting the clinical relevance of amoeboid behavior.

PDAC is not a one-size-fits-all disease; rather, it is marked by substantial diversity, both in terms of genetic mutations and the behaviors of cancer cells. Amoeboid cells are not exclusive to a particular subset of PDAC, as they have been identified in multiple human PDAC cell lines with varying genetic backgrounds. This diversity underscores the adaptability and plasticity of cancer cells when it comes to migration and invasion. Understanding this diversity can have a profound impact on the development of therapeutic strategies. The ability of cancer cells to shift between amoeboid and mesenchymal states offers a window of opportunity for interventions that aim to lock them into a less invasive, less aggressive state.

In a new study published in the peer-reviewed Journal Science Advances led by Professor Victoria Sanz-Moreno from the Barts Cancer Institute at Queen Mary University of London. Discussed the association with mesenchymal traits lies the activity of Myosin II, a molecular motor protein responsible for regulating various cellular processes. Myosin II comes in different isoforms—Myosin IIB and Myosin IIC—that are crucial for the formation of the actin cortex, a structure that influences cell shape and migration. While Myosin IIB localizes at the edge of the cell, Myosin IIC is found toward the cell’s center. Phosphorylation of Myosin II light chain (MLC) reflects its activation and plays a central role in amoeboid behavior, where the activation of Myosin II is higher.

Myosin II is not only a key player in the regulation of amoeboid behavior but also a determinant of drug resistance in PDAC. Inhibition of Myosin II using small molecules such as H-1152 and Y-27632 sensitizes both mesenchymal and amoeboid cells to conventional chemotherapy, such as gemcitabine (Gem). When Myosin II activity is blocked, these cancer cells become more responsive to treatment, offering a potential strategy to enhance the effectiveness of chemotherapy regimens. Importantly, this strategy also extends to improving the survival outcomes in preclinical models, highlighting the therapeutic promise of targeting Myosin II in PDAC.

The realization that Myosin II inhibitors can sensitize PDAC cells to chemotherapy opens a new avenue for treatment. Several studies demonstrate the potential benefits of using Myosin II inhibitors in combination with conventional chemotherapy, highlighting the importance of targeting amoeboid behavior and the associated signaling pathways as an adjunct to established treatment modalities.  A synergistic approach that combines Myosin II inhibitors with chemotherapy offers a twofold advantage. Firstly, it increases the sensitivity of cancer cells to chemotherapy, potentially reducing the required drug doses and minimizing side effects. Secondly, it may help prevent or delay metastasis by locking cancer cells into a less invasive state. By controlling the migratory strategies of PDAC cells, this combination therapy could offer new hope to patients in terms of survival and quality of life.

In addition to enhancing the effectiveness of chemotherapy, targeting Myosin II has the potential to influence the tumor microenvironment’s immunosuppressive properties. Amoeboid pancreatic cancer cells have been shown to secrete immunosuppressive cytokines that hinder the activity of immune cells, particularly T lymphocytes. This immunosuppression creates a barrier for the immune system in recognizing and eliminating cancer cells. By inhibiting Myosin II and the associated immunosuppressive signaling, we can potentially tip the balance in favor of the immune system. This approach may allow immune cells to infiltrate the tumor and mount a more robust attack against cancer cells. In essence, targeting Myosin II not only combats drug resistance but also fosters a more favorable immunological tumor microenvironment.

The discovery of amoeboid behavior and the central role of Myosin II in PDAC metastasis and drug resistance mark a paradigm shift in our understanding and approach to this deadly disease. It highlights the necessity of tailoring therapies to address the diverse migratory strategies that cancer cells employ and the importance of considering the tumor microenvironment as a critical player in metastasis. The emergence of combination therapies that include Myosin II inhibitors reported by Professor Victoria Sanz-Moreno  and colleagues holds great promise for PDAC patients. Not only can these therapies enhance the effectiveness of chemotherapy, potentially extending patient survival, but they also have the potential to rekindle the immune response within the tumor microenvironment.

The study also sheds light on the complexity of cancer cell migration and the plasticity of tumor cells. Pancreatic cancer cells exhibit a spectrum of migratory behaviors, including collective, mesenchymal, and amoeboid modes. The ability of cancer cells to transition between these states in response to the tumor microenvironment and signaling pathways such as ROCK–Myosin II highlights the adaptability and resilience of these cells. This plasticity underscores the challenges in developing effective therapies against metastatic disease, as targeting a single mode of migration may not be sufficient to prevent cancer spread.

The findings in this study open up several potential avenues for further research and therapeutic development. Targeting CD73, either through small molecules or immunotherapeutic approaches, could offer a promising strategy to limit the invasive and immunosuppressive properties of amoeboid pancreatic cancer cells. The study also highlights the importance of understanding the dynamics of cancer cell migration in different microenvironments and the role of signaling pathways like ROCK–Myosin II in regulating these processes. This knowledge could lead to the development of more precise and effective treatments for pancreatic cancer.

In conclusion, this study led by Professor Victoria Sanz-Moreno provides valuable insights into the complex behavior of pancreatic cancer cells and their interactions with the tumor microenvironment. The identification of amoeboid cancer cells, characterized by high CD73 expression and Myosin II activity, as a key driver of invasion, immune evasion, and poor prognosis, offers a potential target for therapeutic intervention. The study underscores the urgent need for innovative approaches to combat pancreatic cancer, a disease that continues to pose a significant challenge to the medical community. The development of targeted therapies that disrupt the signaling pathways driving amoeboid behavior and immunosuppression holds promise for improving the outlook of patients with this aggressive malignancy. Further research in this direction is essential to translate these findings into clinical applications and improve the prognosis of those affected by pancreatic ductal adenocarcinoma.