Dataset Information

Transcriptomics and proteomics reveal distinct biology for lymph node metastases and tumor deposits in colorectal cancer

ABSTRACT: Objective: Both lymph node metastases (LNMs) and tumor deposits (TDs) are included in colorectal cancer (CRC) staging, although knowledge regarding their biological background is lacking. This study aims to compare the biology of these prognostic features, which is essential for a better understanding of their role in CRC spread. Design: Spatially resolved transcriptomic analysis using Digital Spatial Profiling was performed on TDs and LNMs from 10 CRC patients using 1,388 RNA targets, for the tumor cells and tumor microenvironment (TME). Shotgun proteomics identified 5,578 proteins in 12 different patients. Differences in RNA and protein expression were analyzed, and spatial deconvolution was performed. Image-based CMS (imCMS) analysis was performed on all TDs and LNMs included in the study. Results: Transcriptome and proteome profiles identified distinct clusters for TDs and LNMs in both the tumor and TME segment, with upregulation of matrix remodeling, cell adhesion/motility and epithelial mesenchymal transition (EMT) in TDs (all p<0.05). Spatial deconvolution showed a significantly increased number of fibroblasts, macrophages, and regulatory T cells (p<0.05) in TDs. In consistency with a higher fibroblast and EMT component, imCMS classified 62% of TDs as poor prognosis subtype CMS4 compared to 36% of LNMs (p<0.05). Conclusion: Compared to LNMs, TDs have a more invasive state; involving a distinct TME and upregulation of EMT, which are reflected in a more frequent histological classification of TDs as CMS4. These results emphasize the heterogeneity of locoregional spread the fact that TDs should merit more attention both in future research and during staging.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colorectal Cancer Cell

DISEASE(S): Colorectal Cancer

SUBMITTER: Pascal Jansen

LAB HEAD: Michiel Vermeulen

PROVIDER: PXD041625 | Pride | 2023-09-19

REPOSITORIES: Pride

ACCESS DATA

Similar Datasets

Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.

Dataset Information

Transcriptomics and proteomics reveal distinct biology for lymph node metastases and tumor deposits in colorectal cancer

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure