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Mapping proteome changes in recurrent colon cancer reveals a significant immune system signature

ABSTRACT: Background The molecular mechanisms underlying colon cancer development are multifactorial. There is a clinical need for better markers than current TNM stages for stratifying risk of recurrent disease and to guide clinicians in choice of adjuvant treatment. The objective of this study is to evaluate the level of differences between recurrent and non-recurrent colon cancer in five year follow-up by proteomics. We identified 4,805 proteins quantified across all ten groups with at least one unique peptide sequence and 1% FDR. For the cluster analysis, 2919 proteins (61%) appear in two clusters differentiating the tumor and control samples. 54 proteins (1 %) appear in a cluster seemingly differentiating recurrent and non-recurrent cancer. A cut-off strategy with pathway analysis identify 255 proteins (5%) different between recurrent and non-recurrent cancer for the combined TNM2 and TNM3 group. Likewise, we identified 727 proteins (15%) for the TNM2 r+/r- group and 343 proteins (7%) for TNM3 r+/r-, partly with overlapping predicted gene findings. We demonstrate the degree of dissimilarity between recurrent and nonrecurrent cancer in a proteomics dataset. We believe these findings are usable for setting up larger scale experiments in recurrent cancer although the study is underpowered for diagnostic purposes.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon

SUBMITTER: Tian Zhang

LAB HEAD: Joao Paulo

PROVIDER: PXD026630 | Pride | 2022-03-11

REPOSITORIES: Pride

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Project description:Objective: The loss of insulin-secreting β-cells, ultimately characterizing most diabetes forms, demands the development of cell replacement therapies. The common endpoint for all ex vivo strategies is transplantation into diabetic patients. However, the effects of hyperglycemia environment on the transplanted cells were not yet properly assessed. Thus, the main goal of this study was to characterize global effect of brief and prolonged in vivo hyperglycemia exposure on the cell fate acquisition and maintenance of transplanted human pancreatic progenitors. Methods: To rigorously study the effect of hyperglycemia, in vitro differentiated human induced pluripotent stem cells (hiPSC)-derived pancreatic progenitors were xenotransplanted in normoglycemic and diabetic NSG RIP-DTR mice. The transplants were retrieved after one-week or one-month exposure to overt hyperglycemia and analyzed by large-scale microscopy or global proteomics. For this study we pioneer the use of the NSG RIP-DTR system in the transplantation of hiPSC, making use of its highly reproducible specific and absolute β-cell ablation property in the absence of inflammation or other organ toxicity. Results: Here we show for the first time that besides the presence of an induced oxidative stress signature, the cell fate and proteome landscape response to hyperglycemia was different, involving largely different mechanisms, according to the period spent in the hyperglycemic environment. Surprisingly, brief hyperglycemia exposure increased the bihormonal cell number by impeding the activity of specific islet lineage determinants. Moreover it activated antioxidant and inflammation protection mechanisms signatures in the transplanted cells. In contrast, the prolonged exposure was characterized by decreased numbers of hormone+ cells, low/absent detoxification signature, augmented production of oxygen reactive species and increased apoptosis. Conclusion: Hyperglycemia exposure induced distinct, period-dependent, negative effects on xenotransplanted human pancreatic progenitor, affecting their energy homeostasis, cell fate acquisition and survival.

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Mapping proteome changes in recurrent colon cancer reveals a significant immune system signature

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