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Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction

ABSTRACT: Understanding the phenotypic alterations that play a role in differential response to drugs will be pivotal in identifying predictive biomarkers and developing efficacious therapies for advanced CRC. The bulk of research to date has focused on the value of organoids as a predictive tool; some have characterized the transcriptomic profile in relation to drug sensitivity in an effort to identify predictive biomarkers, but only a limited number of studies have used quantitative proteomic analysis to characterize PDOs. Extensive literature indicates that transcriptomic and proteomic expression profiles lack correlation due to significant post-transcriptional regulation, which could explain why RNA signatures are rarely useful as drug response predictors in the clinic. In this study we generated PDO models from advanced CRC patients including heavily pre-treated patients and a model of microsatellite instable- (MSI) high CRC, for which pre- and post chemotherapy liver disease PDOs were established and characterized to ensure biological fidelity with the original tumors. Our main objective was to integrate functional drug assays on PDOs with proteotranscriptomic study to explore the mechanisms underlying drug response. To this end, we used SWATH-MS (sequential window acquisition of all theoretical mass spectrometry), a highly accurate proteomic quantification technique and a bulk RNA-seq analysis. This strategy could represent a useful tool to discover new therapeutic targets in advanced CRC and to guide personalized therapies.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Colon Cancer

SUBMITTER: Luz Valero

LAB HEAD: Josefa Castillo

PROVIDER: PXD038149 | Pride | 2025-02-03

REPOSITORIES: pride

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Project description:Since the first human conceived through in vitro fertilisation in 1978, over 8 million babies have been born by assisted reproductive technologies (ART). Although most ART babies and children seem healthy, in recent years, several human and animal model studies have evidenced a potential impact of ART on long-term development. However, the long-term follow-up data in this field is still limited. Till now, studies are mainly focused on techniques such as in vitro fertilisation or in vitro culture, being the information from gametes/embryos cryopreservation field practically missing. Herein, we have developed an animal model to determine whether vitrified-thawed embryo transfer procedure has long-term consequences over the offspring. The birth weight, growth performance and adult body weight of the rabbits derived from vitrified-thawed embryos was compared with that of the naturally-conceived animals. In adulthood, the liver, heart, kidneys, spleen, lungs, gonads and adrenal glands of the males were weighed and compared. Moreover, some haematological and biochemical parameters were assessed on peripheral blood. Besides, some liver samples were obtained to perform a comparative proteomic study. The embryo vitrification-transfer process modified the birth weight and the growth pattern of the offspring, reducing the growth performance in a sex-specific manner. In adulthood, animals derived from vitrified embryos showed a significantly lower body, liver and heart weight. Molecular analyses revealed that vitrified-thawed embryo transfer procedure triggers concordant reprogramming of the liver proteome. The most relevant metabolic alteration denoted by the protein profile was that related to the oxidative phosphorylation, suggesting an impaired oxidative metabolism in the mitochondria. Furthermore, hints of dysregulation in the zinc and lipid metabolism were identified. These results evidence long-term consequences in the offspring derived from cryopreserved-transferred embryos and represented an evident example of the phenotypic plasticity exhibited by the mammalian embryo.

Project description:The DNA, its epigenetic information and signals from the direct environment, all work together to orchestrate the development of the single fertilized oocyte into a new individual. The concept of developmental programming, attributed to the embryonic plasticity, suggests that the early life environment influences offspring characteristics in later life, but also further generations. There is increasing awareness about the use of Assisted Reproductive Technologies (ART), because, due to its high inefficiency mimicking in vivo optimal conditions, implies an extraordinary change in the environment where the beginning of a new organism takes place. Here we assessed the transgenerational effects of the cryopreserved embryo replacement on a maternal tract using the rabbit as a model. Then, one progeny derived from vitrified-transferred embryos (VT group) was compared to a cohort of animals naturally-conceived (NC group). A multi-omic approach (metabolome, proteome and epigenome) were addressed on the liver tissue in order to complete or previous phenotypic and transcriptomic characterization of F3 animals. LC-ESI-MS and LC-APCI-MS analysis were performed to interrogate the semi-polar and non-polar metabolomes, respectively. For the proteomic study, the analysis was carried on by LC-SWATH-MS. Finally, genome-wide DNA methylation profiling was studied by MBD-Seq. The healthy state was evaluated by a haematological and biochemical analysis of the peripheral blood. Targeted and untargeted metabolome analysis revealed a global metabolome alteration in the VT livers, particularly for those pathways related with the lipid metabolism. Here was detected some disturbances in the metabolism of long-chain polyunsaturated fatty acids (LC-PUFA), which was corroborated by the proteomic data. Functional analysis of the subset of proteins that differs between VT and NC livers revealed significant changes in the metabolism of the linoleic (LIN) and arachidonic (ARA) acids, whose downstream consequences directly was related with dysregulations in the growth and immune system responses. Overall results denoted that these metabolic disturbances participated in a complex network of physiological pathways that together promotes the phenotypic deviations currently observed after an embryo cryopreservation-transfer procedure (CTP). The underlying hypothesis supported by our results, is that these developmental deviations respond to changes in the epigenome, as consequence of direct perturbation of the reprogramming process by ART, which are dragged until adult life and inherited by further generations. Changes in the epigenetic suggested possible interactions between lipid and apoptotic pathways that jointly reprograms the physiology of the liver. However, based on peripheral blood parameters, the healthy status of VT animals was comparable to that of the NC group. Our data provides valuable information about the transgenerational long-term molecular effects of the embryo CTP using high-throughput sciences, which should highlight the need to study ART not only to increase pregnancy rates, but also to use ART in the safest way possible.

			Action	DRS
	AC_210616_L1A1.wiff	Wiff
	AC_210616_L1A1.wiff.scan	Wiff
	AC_210616_L1A2.wiff	Wiff
	AC_210616_L1A2.wiff.scan	Wiff
	AC_210616_L1A3.wiff	Wiff

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Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction

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