Squamousness gain defines pancreatic ductal adenocarcinoma hepatic metastases phenotype, and gemcitabine response

FRAUNHOFFER, NICOLAS A; ANALIA MEILERMAN ABUELAFIA; TEYSSEDOU, CARLOS; CHULUYAN, EDUARDO; BIGONNET, MARTIN; PALAZZO, LAURENT; GAYET, ODILE; NICOLLE, REMY; CROS, JEROME; IOVANNA, J; DUSETTI, NELSON

EUROPEAN JOURNAL OF CANCER

ELSEVIER SCI LTD

Lugar: Amsterdam; Año: 2021

0959-8049

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with asurvival rate of less than 7%, mainly due to the hepatic metastatic spread. Despite the impor-tance of understanding PDAC metastases, central questions remain concerning their biologyand chemosensitivity. Moreover, the transcriptomic divergence between primary tumor (PT)and hepatic metastases (HM) has been poorly studied and without a clear dissection of theconfounding tumoral-surrounding tissue. Methods: Here, to unravel key biological features not biased by the surrounding tissue, we implemented a blind source separation based on independent component analysis, ProDenICA,on a treatment-naıve cohort of PDAC paired samples and a cohort of 305 resectable patients.In addition, a time-lapse experiment was performed to assess the gemcitabine chemosensitivityprofile between the PT and HM. Results: We identified HM?s specific transcriptomic characteristics related to the upregulationof cell cycle checkpoint, mitochondria activity, and extracellular matrix reorganization, whichcould be associated with metastatic niche adaptation mechanisms. Furthermore, squamouslineage emerged as a key feature linked with adownregulation in the epithelial-to-mesenchymal program that can stratifies PDAC HM independent of the classical/basal-likespectrum. Remarkably, we also demonstrated that gemcitabine response is influenced bythe squamous profile, being the HM more refractory to the treatment than the PT.Conclusions:These results pointed out divergent HM aspects compared to PT and allowedtheir stratification through the squamous lineage. Moreover, we unravel a clinical actionablesquamous signature that predicts the gemcitabine response