Research finds periostin facilitates nerve invasion in pancreatic cancer — Evidence Review

A new study from Brazil identifies periostin, a protein produced by pancreatic stellate cells, as a key driver of early nerve invasion in pancreatic cancer, potentially explaining the tumor’s rapid spread and resistance to treatment. Most related studies support the central role of stromal remodeling and tumor-stroma interactions in enabling nerve invasion and metastasis, lending further credibility to these findings (original source).

• Evidence from multiple studies confirms that perineural invasion (PNI) is facilitated by complex interactions between cancer cells and the surrounding microenvironment, including proteins such as L1CAM, MMP1, and HGF pathways, which collectively enhance tumor invasiveness and metastatic potential 1 2 3 14.
• Periostin’s role as an extracellular matrix (ECM) modulator driving cancer cell migration, survival, and metastasis is well-documented in other cancers, with related studies showing that blocking periostin or its signaling pathways can inhibit tumor progression 6 7 8 9 10.
• The new findings align with recent research highlighting the importance of stromal cell-derived factors and ECM remodeling in pancreatic cancer progression and therapy resistance, emphasizing the potential of targeting the tumor microenvironment for improved treatment outcomes 12 14.

Study Overview and Key Findings

Pancreatic cancer is notorious for its aggressive nature and high mortality, largely due to its tendency to invade nerves and spread early—features that make it difficult to diagnose and treat effectively. The study from Brazil offers critical insight into how the tumor microenvironment, particularly the interaction between cancer cells and pancreatic stellate cells, enables cancer cells to invade nearby nerves at an early stage. This research is timely as it leverages advanced single-cell analysis tools to dissect the molecular and spatial dynamics of tumor-stroma interactions, providing new targets for precision therapy.

Property	Value
Organization	Center for Research on Inflammatory Diseases (CRID), Einstein Israelite Hospital, University of São Paulo
Journal Name	Molecular and Cellular Endocrinology
Authors	Carlos Alberto de Carvalho Fraga, Helder Nakaya
Population	Pancreatic cancer samples
Sample Size	24 pancreatic cancer samples
Outcome	Nerve invasion, cancer progression, potential treatment targets
Results	Periostin aids pancreatic cancer cells in nerve invasion.

Literature Review: Related Studies

To contextualize these findings, we searched the Consensus paper database, which contains over 200 million research papers. The following queries were used to identify relevant studies:

1. pancreatic cancer nerve invasion mechanisms
2. periostin role in cancer metastasis
3. pathways pancreatic cancer cell spread

Topic	Key Findings
How do cancer-stroma interactions drive perineural invasion in pancreatic cancer?	- Pancreatic stellate cells and cancer-associated fibroblasts promote perineural invasion via HGF/c-Met and PIAT/YBX1 pathways, facilitating cancer cell migration and neural remodeling 5 12 14. - Stromal remodeling and dense ECM formation create a microenvironment that supports tumor progression, metastasis, and therapy resistance 12 14.
What is the role of periostin and other ECM proteins in cancer metastasis?	- Periostin enhances tumor cell survival, migration, and angiogenesis in various cancers (colon, breast, ovarian, head and neck), acting through pathways such as Akt/PKB and integrin-FAK-Src 6 7 8 9 10. - Targeting periostin or its upstream inducers (e.g., TGF-β) reduces invasion and metastasis in experimental models 7 8 9 10.
Which molecular pathways enable nerve invasion and early metastasis in pancreatic cancer?	- L1CAM, MMP1/PAR1/SP/NK1R, HGF/c-Met/mTOR/NGF, and NMDAR/HK2 pathways are implicated in early perineural invasion, enhancing tumor cell migration and nerve infiltration 1 2 3 4 14. - Non-invasive imaging and molecular markers can detect early PNI and inform prognosis 2 4.
Can targeting the tumor microenvironment improve pancreatic cancer outcomes?	- Disrupting stromal-tumor crosstalk (e.g., via anti-periostin antibodies or pathway inhibitors) suppresses invasion, metastasis, and therapy resistance in preclinical models 8 10 12 14. - Precision medicine approaches targeting the microenvironment may benefit patients with pancreatic and other solid cancers 12 15.

How do cancer-stroma interactions drive perineural invasion in pancreatic cancer?

The new study’s focus on periostin and stellate cells aligns with broader research indicating that tumor-stroma interactions are central to the progression and invasiveness of pancreatic cancer. Stromal cells, particularly pancreatic stellate cells and cancer-associated fibroblasts (CAFs), actively remodel the ECM and secrete factors that facilitate perineural invasion and metastasis.

• Pancreatic stellate cells promote perineural invasion via activation of the HGF/c-Met pathway, increasing cancer cell invasiveness and nerve infiltration 14.
• CAFs contribute to neural remodeling and PNI by transmitting PIAT-associated transcripts, which modulate RNA methylation and gene expression in tumor cells 5.
• Dense ECM and fibrotic stroma create a protective environment that impedes drug delivery and fosters aggressive tumor behavior 12 14.
• The interplay between cancer cells and stromal elements is associated with worse prognosis and higher rates of metastasis 12 14.

What is the role of periostin and other ECM proteins in cancer metastasis?

Periostin emerges as a key ECM protein promoting metastasis across multiple cancer types. In the context of pancreatic cancer, its ability to reshape the ECM and support tumor cell migration is consistent with findings from studies in colon, breast, ovarian, and head and neck cancers.

• Periostin expression is linked to enhanced metastatic growth, survival, and angiogenesis in colon and breast cancers; inhibition of periostin reduces metastasis in experimental models 6 8.
• Stromal-derived periostin, induced by cytokines such as TGF-β, facilitates tumor cell invasion and is associated with poor prognosis in ovarian and head and neck cancers 9 10.
• The integrin-FAK-Src and PI3K/Akt pathways mediate periostin’s effects on cell migration and survival 7 10.
• Targeting periostin or its signaling pathways is a promising therapeutic strategy under investigation in multiple cancers 7 8 10.

Which molecular pathways enable nerve invasion and early metastasis in pancreatic cancer?

Pancreatic cancer cells exploit several molecular pathways to invade nerves and spread early. These include adhesion molecules, proteases, growth factors, and neuronal signaling components that collectively facilitate PNI.

• L1CAM, secreted by Schwann cells and tumor cells, acts as a chemoattractant and stimulates metalloproteinase expression, promoting nerve invasion 1.
• The MMP1/PAR1/SP/NK1R paracrine loop mediates early PNI and can be detected using non-invasive imaging techniques 2.
• HGF/c-Met signaling enhances expression of nerve growth factor and activates the mTOR/NGF axis, driving PNI and metastasis 3 14.
• Glutamate from nerve cells increases glycolysis in tumor cells via NMDAR-mediated signaling, further promoting PNI; dual-targeted nanoparticles are being explored to block this process 4.

Can targeting the tumor microenvironment improve pancreatic cancer outcomes?

Given the central role of the tumor microenvironment in pancreatic cancer progression, therapies that disrupt stromal-tumor interactions show promise in preclinical models.

• Anti-periostin antibodies and pathway inhibitors (e.g., against HGF/c-Met) reduce tumor invasion, metastasis, and drug resistance in animal models 8 10 14.
• Modulating CAF-derived signals (e.g., PIAT/YBX1 axis) impairs neural remodeling and PNI, offering new avenues for intervention 5 12.
• Targeting ECM remodeling and cancer-stroma crosstalk may enhance drug delivery and improve therapeutic efficacy 12 14.
• Precision medicine strategies that incorporate microenvironmental and molecular profiling could enable more personalized and effective treatments for pancreatic and other solid tumors 12 15.

Future Research Questions

While recent advances have illuminated several pathways underlying perineural invasion and tumor-stroma interactions in pancreatic cancer, significant questions remain. Further research is needed to elucidate the precise mechanisms, optimize therapeutic targeting, and determine how these findings translate to clinical benefit.

Research Question	Relevance
Can periostin-targeted therapies effectively reduce perineural invasion and improve survival in pancreatic cancer?	Determining the clinical efficacy of periostin inhibition is critical, as preclinical studies suggest this protein is central to nerve invasion and metastasis 6 8 10.
What are the molecular mechanisms by which pancreatic stellate cells regulate periostin production and tumor invasion?	Understanding how stellate cells modulate periostin and other pro-metastatic factors may reveal new targets for disrupting the tumor microenvironment 12 14.
How do different tumor microenvironment components cooperate to promote perineural invasion in pancreatic cancer?	The interplay between CAFs, stellate cells, immune cells, and ECM proteins remains incompletely defined and may reveal synergistic therapeutic opportunities 5 12 14.
Are biomarkers of perineural invasion detectable in blood or tissue before overt metastasis?	Early detection of PNI could enable earlier intervention, but reliable clinical biomarkers are still lacking 2 4 5.
What are the best strategies to integrate precision medicine tools for targeting the pancreatic cancer microenvironment?	Optimizing the use of molecular profiling and targeted therapies could improve outcomes, but clinical implementation remains a challenge 12 15.