Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling

Abstract

Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.

The role of lipid species in membranes and cancer-related changes

“…As mentioned above, also increased levels of saturated fatty acyl chains in membrane lipids have been coupled to the presence of more lipid rafts. In a recent study of the effects of lysophosphatidylcholine acyltransferase 1 (LPCAT1) in glioblastoma cells, the increase of disaturated PC species, especially PC 32:0, was taken as evidence for the importance of such lipids and lipid rafts for oncogenic signaling [116]. A commentary article concluded that these data in fact were "tying lipid rafts to oncogenic signaling" [117].…”

Novel approach reveals lipid metabolite reduction in nails of breast cancer patients as potential biomarker

“…There are clear understanding on the heightened choline metabolism in cancer cells and tissues that support the progression, invasion and metastasis of cancer cells (9)(10)(11)(12)(13)(14)(15)(16)(17). In other way, cancer cells are known to divert the dietary source including choline to support the metabolic needs of breast carcinoma and other cancer cell types (11)(12)(13)(14)(15)(16).…”

“…Therefore, comprehensive and novel approaches are warranted to meet the requirements of early diagnosis, monitoring of drug response and new modalities of treatment options (3)(4)(5)(6). Therefore, new area of genomics, proteomics, transcriptomics, epigenomic and metabolomics is set to make advancement in exploring novel classes of biomarkers that can assist in the early detection and drug response monitoring avenues in a global context and Indian setting (3)(4)(5)(6)(7)(8)(9)(10).…”

“…The importance of metabolic heterogeneity is seen as one of key factors that contribute towards biomarkers development in breast cancer patients (5)(6)(7)(8)(9)(10)(11). Metabolic heterogeneity encompasses various metabolic adaptations including lipid remodeling by breast cancer cells to suffice the metabolic requirements in the tumor microenvironment (9)(10)(11)(12)(13)(14)(15)(16)(17).…”

“…The importance of metabolic heterogeneity is seen as one of key factors that contribute towards biomarkers development in breast cancer patients (5)(6)(7)(8)(9)(10)(11). Metabolic heterogeneity encompasses various metabolic adaptations including lipid remodeling by breast cancer cells to suffice the metabolic requirements in the tumor microenvironment (9)(10)(11)(12)(13)(14)(15)(16)(17). Therefore, appreciable attempts were made to determine lipid profiles mostly in blood, as it is the viable option to detect early and late stage physiological and pathological changes in breast cancer patients (10)(11)(12)(13)(14)(15)(16)(17).…”