A disease driver of pancreatic cancer reveals a new Achilles heel

The use of chemotherapy to treat pancreatic ductal adenocarcinomas (PDACs) has mixed outcomes on disease progression. The complexity of PDACs acts as a key barrier to effective therapy development. PDACs are divided into basal or classical subtypes based on distinct gene expression programs and cellular features. Of these two subtypes, the basal form is associated with a more aggressive cancer and worse survival than classical. Researchers at Fred Hutchinson Cancer Center sought to better understand disease drivers of the aggressive basal PDAC subtype to inform on new targeted therapy strategies. Their work began by characterizing how an RNA binding protein, LIN28B, drives tumorigenic signaling within these cancer cells and led to an intriguing finding that blocking protein synthesis could be therapeutically beneficial for the aggressive basal subtype of PDAC. Their work was published in Nature Communications.

LIN28B is normally active only during fetal development but is abnormally reactivated in several cancers, including PDAC. To understand the role of LIN28B expression in PDAC tumor initiation, Dr. Sita Kugel’s lab in the Human Biology Division generated a novel mouse model. Since an activating G12D mutation in KRAS—a protein involved in response to growth stimuli—is frequently found in PDACs, the researchers generated mice expressing KRASG12D alone, LIN28B alone, or both KRASG12D and LIN28B together – the K28C mouse. Strikingly, the combination of the fetal RNA binding protein, LIN28B, with mutant KRAS caused a more aggressive disease with earlier metastasis, and reduced survival compared to the KRAS mutant alone. Characterization of the mouse model revealed that the K28C mouse phenocopies the basal disease. It is noteworthy to mention that LIN28B expression alone did not cause any tumors. Next, the researchers wanted to know if the progression of these aggressive cancers in the K28C mouse could be reduced if LIN28B was limited. Their mouse model had LIN28B expression controlled by an inducible system in which they could remove LIN28B in the mice. When LIN28B expression was turned off after tumor initiation, survival of the mice was doubled compared to K28C mice with continued LIN28B expression. These findings highlight the role of LIN28B as an enhancer of KRASG12D PDAC progression that can be reversed (i.e. therapeutic potential) by limiting LIN28B activity.

The researchers continued to dissect the cellular signaling pathways downstream of LIN28B to determine how LIN28B drives this more aggressive disease. Using their mouse models and both basal and classical PDAC cells, the researchers demonstrated that basal PDACs have increased LIN28B and HMGA2, a chromatin-modifier only expressed in the basal subtype. LIN28B is known to increase HMGA2 expression. However, the researcher’s novel finding was that HMGA2, even without LIN28B, was sufficient to drive the growth of basal PDAC cells. It was also known that basal PDACs have increased protein synthesis compared to the classical subtype. Since protein synthesis is an essential process that forms the building blocks needed for cells to proliferate, the researchers also tested the association between HMGA2 expression and global levels of protein synthesis. Excitingly, following these breadcrumbs, they uncovered a key connection. Dr. Stephanie Dobersch, a postdoctoral fellow in the Kugel lab, summarized these critical findings, “We demonstrate that HMGA2 is not only a biomarker of the basal pancreatic cancer subtype but also a driver of its aggressive biology through enhanced protein synthesis. This establishes protein synthesis as a targetable vulnerability in one of the most lethal cancer subtypes.”

A protein synthesis inhibitor, Homoharringtonine (HHT), is an FDA-approved agent used to treat chronic myeloid leukemia. HTT also limits tumor growth in mouse models of lung cancer. The researchers predicted that they would find similar outcomes in their model of basal PDAC since this cancer also depends on protein synthesis. Their findings supported this prediction; HHT treatment reduced tumor volume of basal PDAC but not classical PDAC. These outcomes suggest that therapeutic strategies that block protein synthesis may be beneficial for the basal subtype of PDAC. “As a next step, we are developing a dual [immunohistochemistry] IHC assay to classify basal versus classical PDAC,” shared Dr. Dobersch. “Our goal is to extend this analysis to understand how HMGA2 shapes treatment response and ultimately use it to guide the selection of downstream therapies.” Further characterization of basal and classical subtypes will help improve accurate PDAC classification and continue to inform on effective therapeutic strategies for this complex group of pancreatic cancers.

The spotlighted research was funded by the National Institutes of Health, Swim Across America, German Research Foundation, and American Cancer Society.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Robert Eisenman, Andrew Hsieh, and Sita Kugel contributed to this work.

Dobersch S, Yamamoto N, Schutter A, Cavender SM, Robertson TM, Kartha N, Samraj AN, Doron B, Poole LA, Wladyka CL, Zhang A, Jang GH, Mahalingam AH, Barreto G, Raghavan S, Narla G, Notta F, Eisenman RN, Hsieh AC, Kugel S. 2025. HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity. Nat Commun. 16(1):4866.