A partial epithelial‐mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction

Abstract

Partial epithelial‐mesenchymal transition (p‐EMT) has recently been identified as a hybrid state consisting of cells with both epithelial and mesenchymal characteristics and is associated with the migration, metastasis, and chemoresistance of cancer cells. Here, we describe the induction of p‐EMT in starved colorectal cancer (CRC) cells and identify a p‐EMT gene signature that can predict prognosis. Functional characterisation of starvation‐induced p‐EMT in HCT116, DLD1, and HT29 cells showed changes in proliferation, morphology, and drug sensitivity, supported by in vivo studies using the chorioallantoic membrane model. An EMT‐specific quantitative polymerase chain reaction (qPCR) array was used to screen for deregulated genes, leading to the establishment of an in silico gene signature that was correlated with poor disease‐free survival in CRC patients along with the CRC consensus molecular subtype CMS4. Among the significantly deregulated p‐EMT genes, a triple‐gene signature consisting of SERPINE1, SOX10, and epidermal growth factor receptor (EGFR) was identified. Starvation‐induced p‐EMT was characterised by increased migratory potential and chemoresistance, as well as E‐cadherin processing and internalisation. Both gene signature and E‐cadherin alterations could be reversed by the proteasomal inhibitor MG132. Spatially resolving EGFR expression with high‐resolution immunofluorescence imaging identified a proliferation stop in starved CRC cells caused by EGFR internalisation. In conclusion, we have gained insight into a previously undiscovered EMT mechanism that may become relevant when tumour cells are under nutrient stress, as seen in early stages of metastasis. Targeting this process of tumour cell dissemination might help to prevent EMT and overcome drug resistance. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Lysosomal alkalinization in nutrient restricted cancer cells activates cytoskeletal rearrangement to enhance partial epithelial to mesenchymal transition

“…RNA sequencing analysis of the nutrient rich (NR) and ND Caco-2 cells, which showed the highest EMT score, revealed the activation of autophagy, cell cycle arrest and a decrease in energy generating pathways with ND, as expected, while at the same time differentially regulating a highly connected network of EMT related genes. This network had EGFR and SERPINE1 at its hub, supporting a recent three gene p-EMT signature consisting of EGFR, SERPINE 1 and SOX10 that we identified in nutrient depleted HCT116 cells, which could significantly predict worse disease-free survival (DFS) in multiple CRC patient cohorts [ 28 ]. CRC tumors showing the three gene signature were categorized as Consensus Molecular Subtype (CMS) 4, associated with a metastatic and invasive phenotype [ 36 ].…”

“…The colony formation assay indicated that the number of colonies formed in the NR medium was statistically similar to the number of colonies formed in the ND medium, indicating high viability. We have previously reported similar changes in ND T84 [25] , HT-29 and DLD1 cells [ 28 ]. High cell survival was corroborated by the CAM assay, whereby Caco-2, HCT116 and LoVo cells incubated in the ND medium were capable of forming tumors with comparable size and volume to the cells incubated in the NR medium.…”

“…We have recently reported that nutrient restriction in HCT116 colorectal cancer cells was associated with a p-EMT related gene signature [ 28 ]. Additionally, we have reported increased drug resistance in several different colorectal cancer cell lines incubated in the ND medium [25] .…”

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

“…Tailoring precision medicine approaches to the specific molecular profile of an individual patient’s tumor requires a comprehensive understanding of the unique molecular characteristics of each subtype. The challenge lies in developing therapies that are effective across the spectrum of colorectal cancer subtypes while avoiding generalized approaches that may not be equally beneficial for all patients. , …”

“…The challenge lies in developing therapies that are effective across the spectrum of colorectal cancer subtypes while avoiding generalized approaches that may not be equally beneficial for all patients. 178,179 The evolution of resistance and issues related to drug specificity underscore the need for a dynamic and adaptable approach in precision medicine implementation against colorectal cancer. Continuous monitoring of a patient's molecular profile throughout the course of treatment, incorporating real-time data, and utilizing advanced diagnostic technologies become crucial components of a successful precision medicine strategy.…”