Brazilian USP Researchers Uncover Periostin’s Role in Pancreatic Cancer Invasion

A groundbreaking study led by scientists at the University of São Paulo (USP) has illuminated a critical mechanism behind the aggressive spread of pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), which accounts for about 90% of all pancreatic cancer cases. The research reveals how tumor cells hijack surrounding healthy tissue by inducing pancreatic stellate cells to produce high levels of the protein periostin (POSTN). This protein remodels the extracellular matrix (ECM), creating pathways that enable cancer cells to infiltrate nerves through a process known as perineural invasion (PNI). PNI is a hallmark of PDAC aggressiveness, often occurring early and contributing to rapid metastasis and poor patient outcomes.

The study, published in the journal Molecular and Cellular Endocrinology, analyzed transcriptomic data from nearly 60,000 single cells across 24 PDAC biopsy samples. Led by principal investigator Helder Nakaya, a professor at USP’s Faculty of Pharmaceutical Sciences and senior researcher at Hospital Israelita Albert Einstein, alongside first author Carlos Alberto de Carvalho Fraga and oncologist Pedro Luiz Serrano Uson Junior, the work was conducted at the Center for Research on Inflammatory Diseases (CRID), funded by the São Paulo Research Foundation (FAPESP). This discovery not only explains why PDAC is so lethal but also points to novel therapeutic targets.

Pancreatic cancer remains one of the deadliest malignancies worldwide, with global incidence nearing 510,000 cases annually and mortality rates almost matching that figure. In Brazil, the National Cancer Institute (INCA) estimates around 11,000 new cases and 13,000 deaths each year, underscoring the urgent need for breakthroughs like this one from USP researchers.

The Silent Killer: Why Pancreatic Cancer is So Deadly

Pancreatic ductal adenocarcinoma typically arises in the exocrine cells lining the pancreatic ducts, often without early symptoms, earning it the moniker “silent killer.” Risk factors include smoking, obesity, chronic pancreatitis, diabetes, and genetic predispositions like BRCA mutations. By the time diagnosis occurs—usually via imaging or biopsy—the cancer has frequently metastasized, with only about 10% of patients achieving five-year survival.

In Brazil, PDAC’s impact is amplified by limited early detection tools and healthcare access disparities, particularly outside major cities like São Paulo. USP’s research highlights how PDAC’s unique tumor microenvironment (TME)—a dense, fibrotic stroma—shields cancer cells from immune attacks and chemotherapy drugs like gemcitabine. This desmoplastic reaction, triggered by the tumor, hardens surrounding tissue, further complicating treatment.

Stakeholders, including oncologists and patients’ advocacy groups, emphasize the need for precision approaches. As Dr. Serrano Uson noted, “Perineural invasion is a marker of cancer aggressiveness,” present in over half of early-stage cases, detected only post-surgery.

Decoding Perineural Invasion: The Nerve Pathway to Metastasis

Perineural invasion occurs when cancer cells surround and infiltrate nerve sheaths, using nerves as “highways” for dissemination. Unlike vascular or lymphatic spread in other cancers, PNI allows PDAC cells to evade early detection and travel distantly, seeding metastases in liver, lungs, or peritoneum.

The process unfolds step-by-step:

• Tumor cells secrete signaling molecules that activate nearby pancreatic stellate cells (PSCs), quiescent fibroblasts in the pancreas.
• Activated PSCs produce excessive ECM components, including collagen and fibronectin, stiffening tissue.
• Periostin emerges as a key player, binding integrins on cancer cells to promote migration and survival.
• Enzymes like matrix metalloproteinases (MMPs) degrade barriers, enabling cancer cells to breach nerve perineurium.
• Once inside, cells exploit nerve growth factors for proliferation, amplifying pain and metastasis risk.

This mechanism explains PDAC’s recurrence post-surgery and resistance to therapies.

Periostin and Stellate Cells: The Dynamic Duo in Tumor Reprogramming

Periostin, a matricellular protein, is typically involved in tissue repair and bone formation but becomes hijacked in cancer. In PDAC, PSCs—under tumor influence—upregulate POSTN expression, as confirmed by single-cell RNA sequencing in the USP study. This creates an invasion-permissive niche.

Real-world cases illustrate this: Patients with high stromal periostin levels show worse prognosis, per prior studies. In Brazil, where PDAC mortality exceeds incidence, targeting this axis could transform outcomes. The study’s integration of spatial transcriptomics revealed periostin-positive PSCs clustered near invaded nerves, providing concrete evidence.

For academics exploring stromal biology, USP’s methodologies offer a blueprint. Researchers can pursue similar projects via higher ed research jobs in oncology.

Innovative Methods Powering the USP Discovery

The team employed cutting-edge single-cell transcriptomics and spatial omics on public datasets from 24 PDAC samples, achieving unprecedented resolution. Helder Nakaya explained, “We integrated data from dozens of samples with extremely powerful resolution,” uncovering novel PSC-tumor interactions overlooked originally.

This computational biology approach, common in Brazilian higher ed, leverages tools like Seurat for clustering and validation via immunohistochemistry. Such rigor positions USP as a leader in cancer bioinformatics.

Statistics and Real-World Impact in Brazil

Brazil faces a rising PDAC burden, with INCA projecting sustained 11,000 annual cases through 2025. Regionally, São Paulo sees higher incidence due to lifestyle factors. Globally, PDAC ranks fourth in cancer mortality.

• 5-year survival: ~10%
• Early PNI prevalence: >50%
• Brazilian deaths: 13,000/year
• Global cases: 510,000/year

Stakeholder perspectives vary: Oncologists advocate early screening, while researchers like those at USP push molecular targets. For more on oncology careers in Brazil, explore university opportunities in São Paulo.

Treatment Implications: Targeting Periostin for Precision Oncology

Blocking periostin or depleting PSCs could halt PNI pre-surgery. Ongoing trials test anti-periostin antibodies in breast cancer, adaptable to PDAC. Dr. Serrano Uson envisions, “If we develop antibodies blocking stellate cells, we’ll prevent early invasive capacity.”

Combined with immunotherapies overcoming desmoplasia, this aligns with precision medicine—treating molecular profiles over histology. Brazilian patients could benefit via SUS-integrated trials. Read career advice for academic CVs in this field.

Spotlight on USP’s Oncology Research Ecosystem

USP’s Faculty of Pharmaceutical Sciences and CRID exemplify Brazil’s higher ed excellence, supported by FAPESP. Helder Nakaya’s team builds on prior stromal studies, fostering collaborations. Postdocs and faculty here drive innovations; see postdoc positions.

Recent Advances and Future Outlook

Beyond periostin, Brazilian efforts include Siglec-10 antibodies reactivating immunity and triple-drug combos eliminating tumors in mice. International trials (e.g., anti-fibrotic agents) complement this. By 2030, periostin inhibitors may enter PDAC clinics, improving survival.

Cultural context: Brazil’s unified health system demands accessible therapies. Actionable insights: Advocate genetic screening; researchers, integrate spatial omics.FAPESP Agency Report

Careers in Cancer Research: Opportunities at Brazilian Universities

This study underscores vibrant prospects for bioinformaticians, oncologists, and stromal biologists at institutions like USP. Roles in research assistant jobs or professor positions abound. For advice, visit higher ed career advice.

Photo by Gabriel Rissi on Unsplash

Looking Ahead: Hope from USP’s Breakthrough

The periostin mechanism discovery heralds a new era for PDAC treatment, validating Brazilian higher ed’s global impact. Explore university jobs, higher ed jobs, or career advice to join this fight. Share your thoughts below.