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In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favor of their more robust neighbors. This process is essential for maintaining tissue homeostasis and ensuring the proper functioning of multicellular organisms. However, recent research has shed light on the potential maladaptation of cell competition, leading to the selection and promotion of aggressive cancer cells within the tumor microenvironment.
Tumors are complex entities comprising not only cancer cells but also a diverse array of stroma cells. These stroma cells, including fibroblasts, immune cells, and blood vessels, play a crucial role in supporting tumor growth and progression. Amongst these stroma cells, tumor-associated macrophages (TAMs) have attracted significant attention due to their multifaceted functions within the tumor microenvironment.
A fascinating study published recently has uncovered a novel interaction between TAMs and cancer cells in the context of cell competition. The research, conducted using a mouse model of breast cancer, focused on the role of the oncogene MYC and its impact on TAMs' behavior. MYC is a well-known driver of cancer growth, and its overexpression often correlates with aggressive tumor behavior.
Interestingly, the study found that MYC-overexpressing cancer cells created a unique cellular state known as the "winner" state, which depended on the activity of a cellular signaling pathway called mTORC1. The researchers observed that inhibiting mTORC1 signaling in cancer cells led to reduced tumor growth. However, the surprising twist came when they investigated the effect of a low-protein diet on tumor growth.
To their astonishment, the researchers discovered that a low-protein diet not only inhibited mTORC1 signaling in cancer cells but also activated the transcription factors TFEB and TFE3 in TAMs. These transcription factors play a crucial role in regulating cellular metabolism and are usually associated with cellular stress responses. Activation of TFEB and TFE3 in TAMs resulted in their outcompeting the MYC-overexpressing cancer cells, leading to suppressed tumor growth.
The mechanism behind this unexpected phenomenon involved the sensing of diet-derived cytosolic amino acids by a group of proteins known as Rag GTPases. These proteins, together with the GTPase-activating proteins GATOR1 and FLCN, controlled the activity of TFEB and TFE3 in TAMs. Under the low-protein diet condition, the depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3, and mTORC1, allowing the cancer cells to gain a competitive advantage and promote tumor growth. Conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3, and mTORC1 under normal protein diet conditions, leading to reduced tumor growth.
Furthermore, the researchers identified a crucial regulator of this process, the endolysosomal engulfment regulator PIKfyve. They found that PIKfyve was essential for mTORC1 hyperactivation in both TAMs and cancer cells and their competitive fitness. Disrupting PIKfyve function resulted in impaired cell competition between TAMs and cancer cells, ultimately leading to enhanced tumor growth.
These findings have significant implications for our understanding of tumor biology and the complex interplay between environmental factors and cancer progression. The study highlights the importance of considering the tumor microenvironment as a dynamic ecosystem where various cell populations interact and compete with one another. TAMs, traditionally regarded as pro-tumor immune cells, have now emerged as key players in this competitive landscape, capable of influencing cancer cell fate and tumor growth.
The identification of this novel innate immune tumor suppression pathway opens up exciting possibilities for developing new therapeutic strategies. By targeting the noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signaling in TAMs, it may be possible to enhance their competitive fitness against cancer cells and restrain tumor growth. Further research is needed to explore the clinical potential of manipulating this pathway and to understand its relevance in different cancer types.
In conclusion, the study unraveled a previously unknown mechanism by which environmental factors, such as diet, can influence cancer cell competition. The intricate interplay between MYC-overexpressing cancer cells, TAMs, and the signaling pathways involved provides a fascinating glimpse into the complex biology of tumors. These findings pave the way for further investigations into the tumor microenvironment and offer new avenues for developing innovative therapeutic approaches to combat cancer.