Pancreatic ductal adenocarcinoma (PDAC)

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive form of pancreatic cancer, accounting for ~90% of pancreatic malignancies. It arises from the ductal epithelial cells of the pancreas, which are responsible for transporting digestive enzymes.

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Overview

• Location: Most often in the head of the pancreas

• Behavior: Highly aggressive, with early local invasion and distant metastasis

• Prognosis: Generally poor due to late diagnosis and resistance to therapy

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Epidemiology

• Typically diagnosed between ages 60–80

• Slightly more common in men

• Among the leading causes of cancer-related death worldwide

• Incidence is increasing globally

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Risk Factors

Non-modifiable

• Increasing age

• Genetic predisposition (e.g., BRCA1/2, PALB2, CDKN2A, STK11)

• Family history of pancreatic cancer

Modifiable

• Smoking (strongest environmental risk factor)

• Chronic pancreatitis

• Obesity

• Long-standing type 2 diabetes

• Heavy alcohol use (indirectly, via pancreatitis)

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Pathogenesis

PDAC develops through a stepwise progression from precursor lesions:

• PanIN (Pancreatic Intraepithelial Neoplasia) → invasive carcinoma

• Common genetic alterations:

  • KRAS (>90% of cases)

  • CDKN2A (p16)

  • TP53

  • SMAD4

The tumor microenvironment is characterized by a dense desmoplastic stroma, which limits drug penetration and contributes to treatment resistance.

The Molecular Biology of pancreatic ductal adenocarcinoma (PDAC).

1. Cells of Origin & Precursor Lesions

PDAC arises from pancreatic ductal epithelium or acinar cells that undergo acinar-to-ductal metaplasia (ADM) under inflammatory stress.

Key precursor lesions

• PanIN (pancreatic intraepithelial neoplasia) – most common

• IPMN and MCN (less commonly progress to PDAC)

Progression follows a stepwise accumulation of genetic alterations.

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2. Core Driver Mutations (“The Big Four”)

Over 95% of PDACs harbor mutations in at least one of these genes:

KRAS (≈90–95%)

• Early, initiating event

• Constitutive activation of RAS signaling

• Common mutations: G12D, G12V, G12R

• Activates:

  • MAPK pathway (RAF → MEK → ERK)

  • PI3K–AKT–mTOR pathway

  • Ral-GDS signaling

• Promotes proliferation, survival, metabolic rewiring

KRAS addiction is a hallmark of PDAC

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CDKN2A (p16^INK4A^) (≈90%)

• Tumor suppressor gene

• Loss via mutation, deletion, or promoter methylation

• Results in unchecked CDK4/6 activity

• Leads to G1–S cell cycle progression

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TP53 (≈70%)

• Late event in progression

• Loss of DNA damage checkpoint

• Gain-of-function mutant p53 promotes:

  • Genomic instability

  • Invasion and metastasis

  • Chemoresistance

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SMAD4 (DPC4) (≈50%)

• Mediates TGF-β signaling

• Loss shifts TGF-β from tumor-suppressive to pro-metastatic

• Strongly associated with widespread metastatic disease

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3. Additional Genetic & Epigenetic Alterations

DNA Damage Repair Defects

• BRCA1/2, PALB2, ATM

• Present in ~10–15% (germline + somatic)

• Confer:

  • Sensitivity to platinum chemotherapy

  • Responsiveness to PARP inhibitors

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Chromatin Remodeling Genes

• ARID1A, KDM6A, SMARCA4

• Affect transcriptional regulation and lineage plasticity

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Epigenetic Changes

• DNA methylation of tumor suppressors

• Histone modifications driving oncogene expression

• Super-enhancer activation of KRAS-driven programs

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4. Signaling Pathways Dysregulated in PDAC

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5. Tumor Microenvironment (TME): A Defining Feature

Desmoplastic Stroma

• Makes up up to 90% of tumor mass

• Composed of:

  • Cancer-associated fibroblasts (CAFs)

  • Stellate cells

  • Extracellular matrix (collagen, hyaluronan)

Functions

• Physical barrier to drug delivery

• Promotes hypoxia

• Secretes growth factors (TGF-β, IL-6)

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Immune Landscape

• Immunosuppressive

• Dominated by:

  • MDSCs

  • Tumor-associated macrophages (M2)

  • Regulatory T cells

• Sparse cytotoxic T cells → explains poor response to checkpoint inhibitors

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6. Metabolic Reprogramming

PDAC cells survive in hypoxic, nutrient-poor conditions by:

• Enhanced aerobic glycolysis

• Macropinocytosis of extracellular proteins

• Autophagy dependence

• Altered glutamine metabolism (KRAS-driven)

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7. Molecular Subtypes

Transcriptomic profiling identifies subtypes with prognostic relevance:

Classical

• High epithelial gene expression

• Better prognosis

• More chemo-sensitive

Basal-like / Squamous

• EMT markers

• TP53 mutations

• Worse prognosis

• Chemoresistant

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8. Metastasis Biology

• Early dissemination (even before overt tumor formation)

• EMT driven by TGF-β, ZEB1, SNAIL

• Circulating tumor cells with stem-like features

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9. Therapeutic Implications

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10. Why PDAC Is So Lethal (Molecularly)

• Early KRAS-driven oncogenesis

• Profound stromal protection

• Immune evasion

• Genomic instability without actionable drivers

• Rapid metastatic competence

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Clinical Presentation

Early disease is often asymptomatic. When symptoms occur, they may include:

• Painless jaundice (especially tumors in the pancreatic head)

• Weight loss and anorexia

• Epigastric or back pain

• New-onset or worsening diabetes

• Fatigue

• Pale stools and dark urine

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Diagnosis

• Imaging: Contrast-enhanced CT (pancreatic protocol) is first-line

• MRI/MRCP: Helpful for ductal anatomy

• Endoscopic ultrasound (EUS) with biopsy for histologic confirmation

• CA 19-9: Tumor marker (useful for monitoring, not screening)

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Staging

Uses the TNM system and is often categorized clinically as:

• Resectable

• Borderline resectable

• Locally advanced (unresectable)

• Metastatic

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Treatment

Surgical

• Surgical resection (e.g., Whipple procedure) is the only potentially curative option

• Only ~15–20% of patients are resectable at diagnosis

Systemic Therapy

• Adjuvant or neoadjuvant chemotherapy

  • Common regimens: FOLFIRINOX, gemcitabine + nab-paclitaxel

• Targeted therapy in select patients (e.g., PARP inhibitors for BRCA-mutated tumors)

Radiation

• Used selectively, often for local control

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Prognosis

• 5-year survival: ~10–12% overall

• After successful resection and adjuvant therapy: ~25–30%

• Prognosis depends on stage, performance status, and tumor biology

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Research & Emerging Areas

• Early detection strategies (liquid biopsy, biomarkers)

• Immunotherapy combinations (PDAC is largely immunotherapy-resistant)

• Targeting the tumor stroma and metabolic pathways

• Personalized medicine based on molecular profiling

How Does PDAC Compare With Other Adenocarcinomas

1. Shared Adenocarcinoma Features

Across organs, adenocarcinomas typically share:

• Origin from glandular epithelium

• Stepwise carcinogenesis with driver mutations

• Hallmarks of cancer (genomic instability, evasion of apoptosis, metastasis)

• Ability to form gland-like structures histologically (early disease)

PDAC diverges in how early and aggressively these features appear.

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2. Driver Mutation Landscape (Key Difference)

Why PDAC is different

• Near-universal KRAS dependence

• Loss of SMAD4, rare in other adenocarcinomas

• Few druggable oncogenes

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3. Timing of Metastasis

PDAC cells acquire metastatic competence early, even at PanIN stages.

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4. Tumor Microenvironment (Most Distinctive Feature)

Stromal Content

PDAC stroma:

• Dense collagen and hyaluronan

• High interstitial pressure

• Collapsed blood vessels

➡️ Chemotherapy penetration is uniquely impaired

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Immune Environment

PDAC is a “cold tumor”, unlike many other adenocarcinomas.

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5. Metabolic Adaptation

PDAC cells:

• Thrive in hypoxia and nutrient deprivation

• Depend on autophagy and macropinocytosis

• Exhibit unique KRAS-driven glutamine rewiring

Most other adenocarcinomas rely more on:

• Aerobic glycolysis (Warburg effect)

• Better vascularization

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6. Precursor Lesions

PDAC precursors are:

• Microscopic

• Hard to detect

• Rarely screened

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7. Molecular Subtypes (Comparative)

 PDAC subtypes lack strong therapeutic stratification so far.

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8. Therapeutic Responsiveness

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9. Survival Outcomes

PDAC is an outlier in lethality, not just another adenocarcinoma.

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10. Conceptual Summary: Why PDAC Is Unique

PDAC combines:

1. Early KRAS-driven oncogenesis

2. Early metastatic ability

3. Extreme stromal protection

4. Profound immune evasion

5. Metabolic resilience

6. Lack of druggable targets

Other adenocarcinomas may share some of these features—PDAC has all of them simultaneously.