Abstract
Abstract
Colorectal cancer (CRC) is the third most common cancer in North America, and the third leading cause of cancer-related death. About 50% of patients will be diagnosed with CRC liver metastasis (CRCLM) during the course of their disease. We have identified two major histological growth patterns (HGP) in CRCLM resected from patients. In the desmoplastic HGP (DHGP), the tumor cells are enclosed within a desmoplastic stromal ring, physically separating them from the normal liver tissue. In the replacement HGP (RHGP), the tumor cells replace normal hepatocytes without disrupting adjacent cells or structures within the liver parenchyma. We have recently shown that patients with RHGP lesions who received neoadjuvant bevacizumab plus chemotherapy had a worse pathological response and five-year overall survival. Our group has also shown that RHGP CRCLM is resistant to anti-angiogenic therapy due to it promoting vessel co-option as a means of tumor vascularization, rather than VEGF-dependent angiogenesis as seen in DHGP. However, the molecular mechanisms that drive the CRCLM HGPs remain unknown.
This project aims to shed light on the biological processes that underlie the diversity of HGPs, with an emphasis on the key genes and pathways that support the RHGP. To test this, we have: Aim 1) performed RNAseq on chemonaïve RHGP and DHGP CRCLM lesions to identify pathways that are significantly upregulated in the RHGP. We have validated these genes via real-time PCR (RT-PCR), and a subset by immunohistochemistry (IHC). Aim 2) To further refine the RHGP gene signature and to examine the effects of cell-cell interactions on hepatocyte and tumor cell gene expression, individual cells have been isolated from distinct regions within RHGP CRCLM tissues using laser capture microdissection (LCM), followed by single-cell transcriptomics analyses.
Our preliminary data have identified three major pathways with differentially expressed genes: i. cell motility, ii. cell junctions, and iii. ECM-receptor interactions, which are upregulated in RHGP relative to the DHGP and normal liver. A panel of RHGP-specific genes has been identified and validated via RT-PCR. We selected a subset of these genes and are performing IHC to further validate and locate their expression. We have also performed LCM and are in the process of performing transcriptomics analyses – the data will be presented.
We expect to gain some insight into the mechanisms responsible for driving and/or maintaining the RHGP lesions. In the longer term, this work will result in identification of targets in the HGPs that will help stratify patients in terms of treatment. It would appear that we have fewer treatment options for the RHGP patients and it would be important to utilize the data to develop new treatment strategies for those patients. These new therapies would lead to further clinical trials.
Citation Format: Vincent Palmieri, Anthoula Lazaris, Hussam Alamri, Abdellatif Amri, Nisreen Ibrahim, Pablo Zoroquiain, Peter Vermeulen, Peter Metrakos. Metastatic colorectal cancer: characterization of distinct histological growth patterns which demonstrate different response to current treatment regimes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2834. doi:10.1158/1538-7445.AM2017-2834