Research

Introduction to our research

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of human cancers, with a five-year survival rate that remains below 13% despite decades of progress against other tumor types. Its lethality stems from several converging features: most patients present with locally advanced or metastatic disease because early symptoms are vague or absent; credentialed biomarkers for early detection of the disease remain scarce; and cancer cells are enveloped by an unusually dense, fibrotic stroma that fosters an immunosuppressive microenvironment. Tumor cells adapt to this hostile niche through metabolic reprogramming, while the aging pancreas and its shifting immune landscape further shape how disease progresses from normal tissue to invasive cancer. Together, these features have made pancreatic cancer notoriously resistant to conventional therapies. Meeting this challenge requires research spanning the earliest steps of tumor formation to the design of new detection and treatment strategies — the translational research portfolio that defines much of the work within our laboratory.

Key references:

(1) Halbrook, Lyssiotis, Pasca di Magliano and Maitra. Pancreatic Cancer: Advances and Challenges. Cell 2023
(2) Makino et al. Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas. GUT 2024.

Biology of Pancreatic cancer precursors

Nearly all pancreatic cancers arise from microscopic precursor lesions — pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) — that can take years to progress to invasive disease, offering a critical but poorly understood window for interception. Our laboratory studies biologically relevant models of this progression, including genetically engineered mouse models that recapitulate the stepwise evolution from normal epithelium through precursor lesions to carcinoma. For example, our laboratory has developed the first models of cystic precursor lesions of pancreatic cancer that both genocopy and phenocopy the multistep progression characteristic of the cognate human disease. These models allow us to map the genetic, epigenetic, and microenvironmental changes that accompany malignant transformation, and to test which changes are true drivers of progression rather than bystanders. The use of these genetically engineered models – combined with cross species validation studies in patient-derived models such as organoids - underlies many of the ongoing projects in the lab, since understanding how precancer becomes cancer is the foundation for detecting and intercepting the disease earlier. Building on our precancer models, we are also developing and testing interception strategies directly, including newly developed agents targeting mutant KRAS that are designed to eliminate precancerous and early cancer cells before they progress.

Key references:

(1) Hosein et al. Loss of Rnf43 accelerates Kras-mediated neoplasia and remodels the tumor-immune microenvironment in pancreatic adenocarcinoma. Gastroenterology 2022
(2) Makino et al. Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas. GUT 2024.
(3) Chen et al. Long-chain sulfatide enrichment is a metabolic vulnerability in intraductal papillary mucinous neoplasm associated pancreatic cancers. GUT 2025

Spatial heterogeneity in multistep pancreatic cancer progression

Pancreatic cancer does not progress uniformly — even within a single precancerous lesion, or within one patient’s metastases, tumor cells can display strikingly different molecular identities. Our laboratory uses spatial transcriptomics and proteomics, which preserves the physical location of expression within intact tissue, to map this heterogeneity across every stage of disease, from the earliest precursor lesions to advanced metastatic disease. In intraductal papillary mucinous neoplasms (IPMN), a common precursor of pancreatic cancer, we identified the transcription factor NKX6-2 as a driver of a gastric-type, indolent cell state, helping explain why some IPMNs remain low risk while others progress to invasive cancer. At the other end of the disease spectrum, we generated spatially resolved transcriptomic maps of primary tumors and matched liver, lung, and peritoneal metastases obtained through rapid autopsy, revealing that pancreatic cancer cells shift into distinct lineage states as they colonize different organs. Together, these studies show that molecular heterogeneity in pancreatic cancer is not random noise but a structured, spatially organized feature of the disease — one that we believe holds essential clues for predicting which precancers will progress and which metastases will resist therapy, and that we are using to build a more complete atlas of pancreatic cancer evolution from precancer to metastasis. Increasingly, our studies in this area incorporate artificial intelligence (AI) as a modality for enhancing pattern recognition, biological stratification, and predicting actionability of spatial data.

Key references:

(1) Min et al. AI powered deep visual proteomics reveals critical molecular transitions in pancreatic cancer precursors. Cancer Discovery 2026
(2) Pei, Min et al. Spatial mapping of transcriptomic plasticity in metastatic pancreatic cancer. Nature 2025
(3) Sans et al. Spatial transcriptomics of intraductal papillary mucinous neoplasms of the pancreas identifies NKX6-2 as a driver of gastric differentiation and indolent biological potential. Cancer Discovery 2023

Harnessing the “RAS revolution” in pancreatic cancer

As part of the Perlmutter Cancer Center’s “KRAS Excellence Initiative (KRAS-X)”, we have continued to be engaged in translational research projects related to mechanisms of RAS inhibitor resistance in pancreatic cancer. The PCC is home to a larger and growing number of clinical trials of KRAS inhibitors (monotherapy and combination therapies) in both the advanced and localized disease space, led by our GI medical oncologists in collaboration with multidisciplinary providers (surgery, radiation oncology and gastroenterology). The correlative studies performed under the umbrella of these trials will inform us regarding prevalent resistance mechanisms to this class of agents, and future combinations that can be deployed to sustain responses. The Maitra lab is sitting at the epicenter of these correlative studies (many of which are orchestrated by Dr. Peter Yu in the Maitra Lab), and include tissue and blood-based longitudinal biopsies, generation of ex vivo organoid and xenograft models, and multimodal profiling. Many of these studies involve multicenter collaborations, and partnerships with our industry colleagues.

Key references:

(1) Aguirre, Stanger and Maitra. Hope on the horizon: KRAS inhibition is creating a new treatment paradigm in pancreatic cancer. Cancer Res 2024.
(2) Aronchik et al. Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination strategies in pancreatic cancer. Nature Medicine 2026.
(3) McAndrews K et al. An allele agnostic mutant KRAS inhibitor suppresses tumor maintenance signals and reprograms tumor immunity in pancreatic cancer. Science Translational Medicine 2025.

At the Perlmutter Cancer Center’s Gastrointestinal Cancer Center (GICC), we have also embarked on some new and exciting research themes within our laboratory, studying the impact of host factors on pancreatic cancer risk. These research directions build on the premise that despite the widespread prevalence of precancerous lesions in the general population, progression to pancreatic cancer remains uncommon, and requires the confluence of microenvironmental and macroenvironmental influences that facilitate disease progression. Examples of some of our ongoing projects include:
- Aging is the single most important risk factor for pancreatic cancer, and our laboratory investigates why the aging pancreas becomes progressively more susceptible to malignant transformation. Using aged mouse models and human tissue from older patients, we examine how age-related changes in the pancreas — including fibrosis, inflammation, and shifts in immune cell composition — create a microenvironment more permissive to precancerous lesions escaping normal growth control. This work aims to explain why pancreatic cancer incidence rises so sharply after age 60, and to determine whether therapies targeting senescent cells could reduce cancer risk or improve outcomes in older patients. Understanding aging biology is increasingly central to our broader mission of earlier detection and interception. Paradoxically, these studies will also inform why a minor but escalating proportion of cancers develop pancreatic earlier in their lives.
- Other ongoing projects are focusing on the role of diet and microbiome on pancreatic cancer risk, with a particular focus on the interactions between western diets and alterations in the gut microbiome that create an ecosystem conducive to cancer progression. Our studies have identified microbial metabolites that are co-opted within evolutionarily conserved mammalian intracellular pathways, driving cancer progression. These studies involve our leveraging aforementioned ex vivo and genetically engineered models, as well as engineered bacteria. We are also exploring the relationship between nerves and cancer cells within the tumor microenvironment, with a particular focus on the role of cancer-associated and microbial-derived products in cancer-associated pain, a debilitating morbidity of pancreatic cancer. These studies represent a collaboration with our colleagues in the NYU School of Dentistry.

Key Maitra Lab collaborators

Our funders (thank you for supporting our research!)

National Cancer Institute https://www.cancer.gov/

Breakthrough Cancer https://breakthroughcancer.org/

Lustgarten Foundation for Pancreatic Cancer Research https://lustgarten.org/

Pancreatic Cancer Action Network https://pancan.org/

Stephenson Global Pancreatic Cancer Research Institute https://sgpcri.global/

Introduction to our research

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Key Maitra Lab collaborators

Perlmutter Cancer Center and NYU Langone Health

NYU School of Dentrisry

MD Anderson Cancer Center

Our funders (thank you for supporting our research!)