Reprogramming of lipid metabolism in cancer-associated fibroblasts potentiates migration of colorectal cancer cells

Abstract

Metabolic interaction between cancer-associated fibroblasts (CAFs) and colorectal cancer (CRC) cells plays a major role in CRC progression. However, little is known about lipid alternations in CAFs and how these metabolic reprogramming affect CRC cells metastasis. Here, we uncover CAFs conditioned medium (CM) promote the migration of CRC cells compared with normal fibroblasts CM. CAFs undergo a lipidomic reprogramming, and accumulate more fatty acids and phospholipids. CAFs CM after protein deprivation still increase the CRC cells migration, which suggests small molecular metabolites in CAFs CM are responsible for CRC cells migration. Then, we confirm that CRC cells take up the lipids metabolites that are secreted from CAFs. Fatty acids synthase (FASN), a crucial enzyme in fatty acids synthesis, is significantly increased in CAFs. CAF-induced CRC cell migration is abolished by knockdown of FASN by siRNA or reducing the uptake of fatty acids by CRC cells by sulfo-N-succinimidyloleate sodium in vitro and CD36 monoclonal antibody in vivo. To conclude, our results provide a new insight into the mechanism of CRC metastasis and suggest FASN of CAFs or CD36 of CRC cells may be potential targets for anti-metastasis treatment in the future.

Fibroblast Reprogramming in Gastrointestinal Cancer

“…For example, activated PSCs showed a remodeled and increased lipid secretome and produced lysophospatidylcholines, which support membrane lipid synthesis, while they were further converted to LPA via autotaxin enzymatic activity to facilitate tumor growth (Auciello et al, 2019). Similarly, CAFs in CRC accumulated fatty acids and phospholipids via an increase in fatty acid synthase (FASN), and were then transferred to cancer cells to induce their migration (Gong et al, 2020).…”

Metabolic Reprogramming of Fibroblasts as Therapeutic Target in Rheumatoid Arthritis and Cancer: Deciphering Key Mechanisms Using Computational Systems Biology Approaches

“…As in RASFs, lipid metabolism is also shown to play a role in CAFs activation and pathological characteristics. Fatty acids synthase (FASN), a crucial enzyme in fatty acids synthesis, was found to be significantly increased in CAFs, whereas CAF migration was blocked by knockdown of FASN in colorectal cancer [ 93 ]. CAFs are also able to transfer a significant number of proteins and lipids to adjacent cancer cells, thereby contributing to sustain the high proliferation rate of tumor cells.…”

“…CAFs are also able to transfer a significant number of proteins and lipids to adjacent cancer cells, thereby contributing to sustain the high proliferation rate of tumor cells. Pancreatic stellate cells (PSCs) derived CAFs are shown to secrete abundant lysophosphatidylcholines (LPCs) in the activated fibroblastic state [ 93 ]. Finally, CAFs can produce glutamine, which is shown to increase autophagy of fibroblasts, a potential energy source for promoting the activity of mitochondria in cancer cells.…”

Obesity-Related Fatty Acid and Cholesterol Metabolism in Cancer-Associated Host Cells

“…Higher FASN activity in CAF identified its role as FAs supplier in breast cancer (Lopes-Coelho et al, 2018). A recent study using lipidomic profiling showed that CAFs provide fatty acyl, long-chain, and unsaturated FAs for colorectal cancer tumor cell development (Gong et al, 2020). There is still a lack of evidence of lipid synthesis changing CAF phenotypes.…”