Researchers at the University of California, San Diego School of Medicine have discovered a molecular pathway involved in the development of pancreatic tumours. The process may have a role in the disease’s high resistance to therapy and predisposition for metastasis.
The study’s results, published in Nature Cell Biology, discovered that pancreatic tumor-initiating cells must first overcome local “isolation stress” by forming their own tumor-promoting microenvironment, before recruiting nearby cells into this network. New treatments that target this tumor-initiating pathway may be able to slow the development, recurrence, and spread of pancreatic cancer. Pancreatic cancer is one of the deadliest tumours, and it is famously resistant to therapy. Cancer recurrence or metastasis affects nearly all patients.
Cancer cells (those with malignant mutations, known as oncogenes) lose adhesion to other cells and the extracellular matrix (the web of macromolecules that encases and supports all cells) in the early stages of tumour development. Because of this isolation, there is a local scarcity of oxygen and nutrients. Most cells cannot tolerate such isolated stress, but a few of them can.
Tumor-initiating cells (TIC) play an important role in tumour genesis, recurrence, and metastatic dissemination. Their resistance to these early poor settings distinguishes them from other cancer cells. They may adapt to the hard environment, much like cactus in the desert, and create the stage for additional tumour growth.
“Our goal was to understand what special properties these tumor-initiating cells have and whether we can control the growth and spread of cancer by disrupting them,” said senior study author David Cheresh, PhD, Distinguished Professor and vice chair of the Department of Pathology at UC San Diego School of Medicine and a member of the UC San Diego Moores Cancer Center.
To find out, first author Chengsheng Wu, PhD, a postdoctoral fellow in Cheresh’s group, treated pancreatic cell lines to a variety of stresses, including low oxygen and sugar levels. He next determined which cells could adapt to the tough environment and examined which genes and chemicals in these cells were altered. The stress-tolerant tumor-initiating cells had lower levels of miR-139-5p, a tumor-suppressive microRNA.
As a result, the lysophosphatidic acid receptor 4 (LPAR4), a G-protein-coupled receptor on the cell surface, was upregulated. “LPAR4 is not normally found on happy cells, but it gets turned on in stressful environments to help the cells survive, which is particularly advantageous for tumor-initiating cells,” said Cheresh.
The researchers discovered that LPAR4 expression stimulated the synthesis of novel extracellular matrix proteins, allowing cancer cells to begin constructing their own tumor-supporting microenvironment.
The new extracellular matrix was especially high in fibronectin, a protein that interacts to transmembrane receptors known as integrins on neighbouring cells. When these cells’ integrins saw fibronectin, they began directing the cells to express their own tumor-initiating genes. These additional cells were eventually drawn into the fibronectin matrix put down by the tumor-initiating cells, and a tumour began to develop.
“Our findings establish a critical role for LPAR4 in pancreatic tumor initiation, and a likely role in other epithelial cancers, such as lung cancer,” said Cheresh, adding, “It is central to tumor-initiating cells’ ability to overcome isolation stress and build their own niche in which tumors can form.”
According to the researchers, solitary stress is not the only way this signalling system may be activated. Chemotherapy medications are also intended to stress cancer cells. Indeed, Cheresh’s team discovered that standard-of-care chemotherapeutics were also upregulating LPAR4 in cultured tumour cells and pancreatic tumours in animals. According to the researchers, this might explain how such tumour cells gain stress tolerance and medication resistance.
Further research revealed that employing integrin antagonists to prevent cells from using the fibronectin matrix reversed the stress tolerance benefit of LPAR4 expression. Thus, the authors propose that targeting the LPAR4 pathway or interrupting the fibronectin/integrin connection might be useful in limiting pancreatic tumour development, dissemination, and treatment resistance.
“We can think of tumor-initiating cells as being in a transient state that can be induced by different stressors, so our clinical goal would be to prevent oncogenic cells from ever entering this state,” said Cheresh, adding, “Now that we’ve identified the pathway, we can assess all the different ways we can intervene.”
A novel medicine targeting this route, according to the researchers, might be used as a preventive in people at high risk of getting the illness, or to prevent new tumours from growing in cancer cases with a high possibility of spreading. Combining the novel medicine with current chemotherapeutics that stress mature tumour cells may help reduce the consequences of drug resistance and make cancer therapies more successful, according to the scientists.
“Treating cancer can feel a little like whack-a-mole but if we have two or three hammers and we know where the moles are going to pop up next, we can beat the game,” said Cheresh.
