Background: A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment. Methods: Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRI-NOX treated metastatic tumours. Findings: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207À0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113À0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001). Interpretation: PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.

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Motivation: Quantification of tumor heterogeneity is essential to better understand cancer progressionand to adapt therapeutic treatments to patient specificities. Results: We present DECONbench, a web-based application to benchmark computational methods dedicated to quantify of cell-type heterogeneity in cancer. DECONbench includes benchmark datasets, computational methods and performance evaluation. It allows submission of new methods. Availability and implementation: DECONbench is hosted on the open source codalab competition platform. It is freely available at: https://competitions.codalab.org/competitions/23660. Supplementary information: Additional information is available online and on our website: https://cancer-heterogeneity.github.io/deconbench.html. 2020 program (grant 826121, iPC project, [JM]).

The rod-shaped adult cardiomyocyte (CM) harbors a unique lateral membrane surface architecture with periodic crests, relying on the presence of subsarcolemmal mitochondria (SSM) with unknown role. Here, we investigate the development and functional role of CM crests during the postnatal period. Using high-resolution imaging, biochemical, immunocytochemical studies in rodents, we demonstrate that CM crest maturation occurs late between postnatal day 20 (P20) and P60 (young adult), after the onset of the CM rod-shape, through both SSM biogenesis, swelling and crest-crest lateral interactions between adjacent CMs, thus promoting tissue compaction. Transcriptomics confirmed this specific P20-P60 late developmental stage that targets all cardiac cell populations. At the functional level, we show that the P20-P60 period is dedicated to the improvement of relaxation. It also contributes to a cardiac hypertrophy relying on a substantial increase in both the CM long- and short axes. However, we demonstrate that the P20-P60 lateral crest/SSM maturation contributes specifically to an atypical physiological CM hypertrophy of the short axis, without myofibril addition, but with sarcomere lateral stretching, indicative of lateral stretch-based CM hypertrophy. Mechanistically, using constitutive and conditional CM-specific knock-out (KO) mice, we identified ephrin-B1, a lateral membrane stabilizer, as a determinant of CM crest maturation during the P20-adult window, controlling specifically both the CM lateral stretch and the diastolic function. Interestingly, while young adult CM-specific Efnb1 KO mice essentially exhibit an impairment of the ventricular diastole with preserved ejection fraction and exercise intolerance, they progressively switch toward systolic heart failure with 100% KO mice dying after 13 months. This study characterized for the first time the molecular determinants and the biological implication of the late P20-P60 postnatal developmental stage of the heart in rodents during which, in part, ephrin-B1 specifically regulates the maturation of the CM surface crests and of the diastolic function.