# Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $574,063

## Abstract

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal of all human malignancies. A key
clinical challenge is the propensity of these tumors for early invasion and metastasis. Thus, most patients are
not eligible for resection, and those who are often show recurrent disease. This challenge is compounded by
the absence of methods for early detection of invasive disease and incomplete understanding of the
mechanisms for PDA progression. Our discovery of the fetal RNA-binding protein Lin28b as a major
driver in PDA metastasis provides a framework to address these critical issues in this multiple-PI
proposal. In previous studies, we have found that the oncofetal RNA-binding protein Lin28b is highly
upregulated in PDA, both in murine models and human patient samples. Furthermore, new preliminary data
indicate that Lin28b is specifically upregulated in Circulating Tumor Cells (CTCs) obtained from patients with
early resectable PDA. Based on these findings, we hypothesize that Lin28b drives PDA progression and
metastasis by reprogramming cell differentiation toward a more primitive progenitor-like state, and that
detection of Lin28b in CTCs can serve as a molecular beacon for disease aggressiveness.In order to
test this hypothesis, we will: 1- Characterize Lin28b as a driver of self renewal and tumor progression in human
and murine PDA models. We will take advantage of ex-vivo grown organoids from human CTCs and specific
genetically engineered mouse models of PDA to genetically manipulate Lin28b and determine tumor
propagating cell function and ability to drive PDA progression. 2- Determine the mechanisms through which
Lin28b could drive agressiveness, exploring its downstream targets (linked to the microRNA let-7), and the
biological and metabolic features driven by this oncofetal protein. 3- Evaluate Lin28b as a predictive biomarker
of PDA early disease recurrence, taking advantage of CTCs isolated from human patients undergoing surgical
resection.

## Key facts

- **NIH application ID:** 9876917
- **Project number:** 5R01CA235412-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $574,063
- **Award type:** 5
- **Project period:** 2019-02-19 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9876917

## Citation

> US National Institutes of Health, RePORTER application 9876917, Mechanistic Understanding for the Role of Lin28b in Pancreatic Cancer Progression (5R01CA235412-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9876917. Licensed CC0.

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