• February 2, 2021

    BSWRI Identifies New Molecular Pathway Linking the Tumor Microenvironment and Pancreatic Adenocarcinoma

Tumorigenesis is a complex process regulated by multiple factors in the cancer cells and the surrounding tumor microenvironment. Because the microenvironment can accelerate tumor growth and contribute to therapeutic resistance, there is great interest in developing cancer therapeutics that directly target the microenvironment. Pancreatic adenocarcinoma is an important example of an aggressive and deadly cancer supported by an abundant microenvironment of non-malignant cells. Chemotherapies and targeted therapies only have modest efficacy against pancreatic adenocarcinoma, leading to an overall 5-year survival rate of 9%, and the microenvironment is thought to contribute to this drug resistance. Thus, the pancreatic tumor microenvironment is under active investigation as a source of new possibilities for therapeutic development.

A recent report from researchers at Baylor Scott & White Research Institute (BSWRI) and Xi’an Jiaotong University, China reveals novel signaling events in the tumor microenvironment that can drive increased growth and metastasis of pancreatic cancer cells. Published in April 2020 in Oxidative Medicine and Cellular Longevity, this new work highlights the complex signaling events that regulate pancreatic cancer.

The Tumor Microenvironment

In pancreatic adenocarcinoma, the cancer cells are surrounded by a desmoplastic stroma containing a variety of non-malignant cells, including cancer-associated fibroblasts, endothelial cells, and immune cells. Cancer-associated fibroblasts, which secrete the extracellular matrix components, are often the dominant cell population. Pancreatic stellate cells (PSCs) are progenitors to the cancer-associated fibroblasts. During malignancy, the PSCs release cytokines and growth factors that can support the developing tumor and contribute to drug resistance. Due to their active role in tumorigenesis, PSCs are considered important components of the pancreatic cancer microenvironment.

Role of Caveolin-1 in Pancreatic Cancer

Caveolin-1 (CAV1), a membrane scaffolding and signaling protein, is well-studied in cancer cells and either promotes or suppresses tumor growth depending on the cancer type and the disease stage. In pancreatic cancer, CAV1 expression in the tumor cells is linked to an aggressive phenotype and poor prognosis. However, the role of CAV1 in the tumor microenvironment, and specifically in the PSCs, is not as well understood.

To clarify the role of CAV1 and its downstream signaling events, the researchers simulated pancreatic cancer in a mouse xenograft model using human PSCs and pancreatic cancer cells. When they depleted CAV1 in the PSCs, the pancreatic cancer cells showed increased growth, invasion, and angiogenesis. This finding supports a mechanistic model wherein CAV1 in the tumor microenvironment may suppress cancer growth.

Molecular Mechanisms Regulated by CAV1 Depletion

The researchers went on to identify the molecular mechanisms underlying the link between CAV1 depletion in the PSCs and increased pancreatic cancer cell growth. They showed that loss of CAV1 in the PSCs increased the release of cytokines and cancer-associated signaling molecules, including sonic hedgehog (SHH), matrix metalloproteinase-2 (MMP2), basic fibroblast growth factor (FGF2), and interleukin 6 (IL6). By blocking the signaling from SHH, they then showed that SHH signaling in the cancer cells is an essential mediator linking CAV1 loss and tumor growth. They also established that signaling in PSCs through the transcription factor NRF2 (also known as NFE2L2), as well as reactive oxygen species production, regulate the pro-tumor effects of CAV1 loss. Overall, this work provides new molecular insights into the mechanisms of cancer development and adds further complexity to the role of CAV1 in pancreatic adenocarcinoma.

Translational research at BSWRI

Erxi Wu, PhD, a senior author on this study, is a BSWRI professor at Baylor Scott & White Medical Center – Temple. Dr. Wu’s translational research interests include identifying the molecular mechanisms underlying cancer and neurodegenerative disease and developing novel therapeutics based on these discoveries. He has published over 143 manuscripts related to this work.