KRAS as a Modulator of the Inflammatory Tumor Microenvironment: Therapeutic Implications

Abstract

KRAS mutations are one of the most frequent oncogenic mutations of all human cancers, being more prevalent in pancreatic, colorectal, and lung cancers. Intensive efforts have been encouraged in order to understand the effect of KRAS mutations, not only on tumor cells but also on the dynamic network composed by the tumor microenvironment (TME). The relevance of the TME in cancer biology has been increasing due to its impact on the modulation of cancer cell activities, which can dictate the success of tumor progression. Here, we aimed to clarify the pro- and anti-inflammatory role of KRAS mutations over the TME, detailing the context and the signaling pathways involved. In this review, we expect to open new avenues for investigating the potential of KRAS mutations on inflammatory TME modulation, opening a different vision of therapeutic combined approaches to overcome KRAS-associated therapy inefficacy and resistance in cancer.

Modulation of Fibroblast Phenotype by Colorectal Cancer Cell-Secreted Factors Is Mostly Independent of Oncogenic KRAS

“…In addition to the role of mutKRAS in controlling key cancer activities, it has been shown that its oncogenic signaling extends beyond the cancer cell to orchestrate a pro-tumorigenic microenvironment [ 6 , 7 , 8 , 9 , 10 , 11 ]. Within the tumor microenvironment (TME), immune cells and fibroblasts are amongst the most commonly found cell types [ 6 , 12 ].…”

“…The effect of mutKRAS on the regulation of the tumor immune microenvironment is one of the most well-described non-cancer cell effects. Specifically, mutKRAS immunomodulatory effects have been reported at the level of recruitment, activation and differentiation of immune cells, supporting the pro-tumorigenic role of the immune compartment as well as at the cancer cell level, promoting evasion from immunosurveillance [ 6 , 7 , 8 , 9 , 10 , 11 , 13 ]. The effects of mutKRAS on the modulation of fibroblasts and cancer-associated fibroblasts (CAFs) phenotypes are not well-studied and the majority of the available studies focus on pancreatic cancer [ 6 , 7 ].…”

Effect of TP53 deficiency and KRAS signaling on the bioenergetics of colon cancer cells in response to different substrates: A single cell study

“…Differences in cellular bioenergetics influences how tumor cells interact with immune cells and other cells of the surrounding tumor microenvironment (TME) ( Fu et al, 2017 ). It has been shown that the presence of TP53 and KRAS mutations has strong implications for the function of the surrounding TME ( Michel et al, 2021 ; Nenkov et al, 2021 ; Pereira et al, 2022 ), immune signaling and escape ( Mantovani et al, 2008 ; Hamarsheh et al, 2020 ). Both immune and stromal cells have been shown to be compromised by TP53 - and KRAS -mediated tumor signaling, thereby enhancing tumor development and growth.…”

Modulation of fibroblasts phenotype by colorectal cancer cells-secreted factors is mostly independent of oncogenic KRAS

“…The effect of mutKRAS on the regulation of the tumor immune microenvironment is one of the most well described noncancer cell effect. Specifically, mutKRAS immunomodulator effects, have been reported to occur at the level of recruitment, activation, and differentiation of immune cells, supporting the immune compartment protumorigenic roles, and cancer cell evasion from immunosurveillance [6][7][8][9][10][11]13 . The effects of mutKRAS on the modulation of fibroblasts and cancer associated fibroblasts (CAFs) phenotypes are not so well studied and the majority of the available studies are focused on pancreatic cancer 6,7 .…”

“…Adding to the roll of key cancer activities controlled by mutKRAS, it has been shown that its oncogenic signaling extends beyond the cancer cell to orchestrate a pro -tumorigenic microenvironment [6][7][8][9][10][11] . Within the tumor microenvironment (TME), immune cells and fibroblasts are amongst the most commomly cell types found 6,12 .…”