Abstract
Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers in which high intra-tumor heterogeneity and plasticity makes PDAC poorly responsive to available treatments. Coupling transcriptional profiling with laser capture microdissection of groups of cancer cells defined by distinct histological patterns, we were able to describe three PDAC “morpho-biotypes”. Such morpho-biotypes represent the combined morphological, molecular and functional properties of PDAC cells that coexist, in various proportions, in nearly all patients analyzed. Compared to single cells, our approach, that integrates morphological and spatial features, was able to clearly identify a novel morpho-biotype, primed toward a neural-like lineage differentiation. Only combining the expression of those genes able to discriminate all three morpho-biotypes, we achieved high prognostic power, underscoring the relevance of the co-existence of different cancer populations for clinical assessment. We therefore hypothesize that only combinatorial therapies, that target all the different biotypes simultaneously, can result in an effective cancer treatment. We identified an antiepileptic drug to be the best candidate to interfere with the neuronal-like program we unexpectedly found enriched in one of the PDAC morpho-biotypes. Using this drug with other oncogenic inhibitors specific for the other morpho-biotypes we obtained a complete stop of the tumor progression in a mouse model of xenografted human tumor fragments that maintained tumor heterogeneity. A similar neural progenitor-like signature was recently found enriched in single cell data form neo-adjuvant treated patients. This founding indirectly suggests that the new morpho-biotype we described in treatment-naïve patients could be responsible for the failure of the available treatments. This study not only contributes to our understanding of the effects of the combinatorial treatment, but also provides valuable molecular data for development of improved treatment schemes and histological maps that can guide pathologists’ diagnosis. Citation Format: Giuseppe R. Diaferia, Pierluigi Di Chiaro, Francesca Fiumani, Lucia Nacci, Alessandro Zerbi, Paola Spaggiari, Iros Barozzi, Gioacchino Natoli. Exploiting the neural-like properties of a new pancreatic cancer morpho-biotype for the development of a combinatorial treatment targeting tumor heterogeneity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A092.
Published Version
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