Molecular dissection of CRC primary tumors and their matched liver metastases reveals critical role of immune microenvironment, EMT and angiogenesis in cancer metastasis

Abstract

Metastasis is the primary cause of cancer mortality. the primary tumors of colorectal cancer (cRc) often metastasize to the liver. In this study, we have collected 122 samples from 45 CRC patients. Among them, 32 patients have primary tumors, adjacent normal tissues, and matched liver metastases. thirteen patients have primary tumors without distant metastasis and matched normal tissues. characterization of these samples was conducted by whole-exome and RnA sequencing and SNP6.0 analysis. Our results revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and metastatic tumors. We then assembled gene co-expression networks and identified metastasiscorrelated gene networks of immune-suppression, epithelial-mesenchymal transition (eMt) and angiogenesis as the key events and potentially synergistic drivers associated with cRc metastasis. Further independent cohort validation using published datasets has verified that these specific gene networks are up regulated throughout the tumor progression. the gene networks of eMt, angiogenesis, immune-suppression and t cell exhaustion are closely correlated with the poor patient outcome and intrinsic anti-PD-1 resistance. These results offer insights of combinational strategy for the treatment of metastatic cRc. CRC is the third most common cancer in world with second highest cancer-related mortality worldwide 1. In US alone, it is estimated that approximately 137,000 people are diagnosed, and more than 50,000 are dead from CRC each year. CRC primary tumors often metastasize to the liver, which accounts for most of CRC related death. The molecular mechanism of tumor metastasis remains poorly understood. It is believed to be a multiple step process that includes cells to detach from their original site and invade the neighboring submucosa, extravasate and survive in the vasculature and metastatic site, and eventually reestablish tumor in alien organ 2. Prevention

Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer

“…Furthermore, (likely) pathogenic mutations mainly coincided in the paired samples and were even observed in different patients. This is in line with results from a study analysing primary CRC as well as matching liver metastasis, where also no significant differences regarding copy number variations or mutations leading to deregulation of signalling pathways could be found [ 13 ].…”

The Tumor Microenvironment in Liver Metastases from Colorectal Carcinoma in the Context of the Histologic Growth Patterns

“…A very common approach to study the biology of the metastatic process has been to compare the primary tumor and the metastatic lesions. Although great similarities between both tumors have been described at the genomic level [5], at the transcriptional level, relevant differences that reflect the particular microenvironment of each different location have been determined. The liver, to name a few examples, has exclusive stromal cells at this location, e.g., Kupffer cells, hepatic stellate cells (HSC) and portal fibroblasts (PF).…”

Poly adenosine diphosphate-ribosylation, a promising target for colorectal cancer treatment

“…Then, changes in various cellular systems within the tumor microenvironment can make it possible to lead a favorable direction for adaptation even with excessive cancer cell growth[ 1 , 2 ]. Recent studies reporting on the details of this malignant transformation have revealed that the following molecular biological and genetic changes play an important role in the development and progression of CRC[ 3 ]. The formation of CRC is predominantly associated with genomic instability caused by the gradual accumulation of genetic and epigenetic changes leading to a transformation of normal colon epithelium into colon adenocarcinoma[ 3 , 4 ].…”

“…Recent studies reporting on the details of this malignant transformation have revealed that the following molecular biological and genetic changes play an important role in the development and progression of CRC[ 3 ]. The formation of CRC is predominantly associated with genomic instability caused by the gradual accumulation of genetic and epigenetic changes leading to a transformation of normal colon epithelium into colon adenocarcinoma[ 3 , 4 ]. The phenomena representing genomic instability, such as chromosomal and microsatellite instability, have been studied, and they are reportedly associated with defects in mitosis, telomere stability, and the deoxyribonucleic acid (DNA) damage response.…”